CML

Key clinical point: Bosutinib is effective in patients with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) resistant/intolerant to prior therapy across age groups and the Charlson Comorbidity Index score without the age component (mCCI) scores.

Major finding: A substantial proportion of patients attained or maintained molecular response across age groups and mCCI scores molecular response. Older patients and those with mCCI ≥4 showed a trend towards higher rates of grade 3/4 treatment-related adverse events.

Study details: The data come from the ongoing, phase 4, single-arm, open-label BYOND study examining the safety and efficacy of bosutinib.

Disclosures: The study was sponsored by Pfizer. No data available regarding conflicts of interest.

Source: Gambacorti-Passerini C et al. Poster. Abstract 055. BSH 2020. 2020 Nov 9-14.

Key clinical point: Bosutinib is effective in patients with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) resistant/intolerant to prior therapy across age groups and the Charlson Comorbidity Index score without the age component (mCCI) scores.

Major finding: A substantial proportion of patients attained or maintained molecular response across age groups and mCCI scores molecular response. Older patients and those with mCCI ≥4 showed a trend towards higher rates of grade 3/4 treatment-related adverse events.

Study details: The data come from the ongoing, phase 4, single-arm, open-label BYOND study examining the safety and efficacy of bosutinib.

Disclosures: The study was sponsored by Pfizer. No data available regarding conflicts of interest.

Source: Gambacorti-Passerini C et al. Poster. Abstract 055. BSH 2020. 2020 Nov 9-14.

Key clinical point: Bosutinib is effective in patients with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) resistant/intolerant to prior therapy across age groups and the Charlson Comorbidity Index score without the age component (mCCI) scores.

Major finding: A substantial proportion of patients attained or maintained molecular response across age groups and mCCI scores molecular response. Older patients and those with mCCI ≥4 showed a trend towards higher rates of grade 3/4 treatment-related adverse events.

Study details: The data come from the ongoing, phase 4, single-arm, open-label BYOND study examining the safety and efficacy of bosutinib.

Disclosures: The study was sponsored by Pfizer. No data available regarding conflicts of interest.

Source: Gambacorti-Passerini C et al. Poster. Abstract 055. BSH 2020. 2020 Nov 9-14.

Key clinical point: Personalized treatment selection according to the LEukemia Artificial intelligence Program (LEAP) recommendations for patients with chronic myeloid leukemia in chronic phase (CML-CP) is associated with better likelihood of survival.

Major finding: The LEAP CML-CP recommendation was associated with an improved overall survival  (P less than 001).

Study details: A cohort of CML-CP patients was randomly assigned to training/validation (n = 504) and test cohorts (n = 126). The training/validation cohort was used to develop the LEAP CML-CP model using 101 variables at diagnosis. The test cohort was then applied to the LEAP CML-CP model and an optimum tyrosine kinase inhibitor therapy was selected for each patient.

Disclosures: The study was supported by the University of Texas MD Anderson Cancer Center Support Grant from the National Institutes of Health, the National Institutes of Health/National Cancer Institute under award, the University of Texas MD Anderson MDS/AML Moon Shot, and Leukemia Texas. K Sasaki, EJ Jabbour, F Ravandi, M Konopleva, G Garcia-Manero, JE Cortes,  C DiNardo reported relationships with various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Sasaki K et al. Am J Hematol. 2020 Nov 12.  doi: 10.1002/ajh.26047.

Key clinical point: Personalized treatment selection according to the LEukemia Artificial intelligence Program (LEAP) recommendations for patients with chronic myeloid leukemia in chronic phase (CML-CP) is associated with better likelihood of survival.

Major finding: The LEAP CML-CP recommendation was associated with an improved overall survival  (P less than 001).

Study details: A cohort of CML-CP patients was randomly assigned to training/validation (n = 504) and test cohorts (n = 126). The training/validation cohort was used to develop the LEAP CML-CP model using 101 variables at diagnosis. The test cohort was then applied to the LEAP CML-CP model and an optimum tyrosine kinase inhibitor therapy was selected for each patient.

Disclosures: The study was supported by the University of Texas MD Anderson Cancer Center Support Grant from the National Institutes of Health, the National Institutes of Health/National Cancer Institute under award, the University of Texas MD Anderson MDS/AML Moon Shot, and Leukemia Texas. K Sasaki, EJ Jabbour, F Ravandi, M Konopleva, G Garcia-Manero, JE Cortes,  C DiNardo reported relationships with various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Sasaki K et al. Am J Hematol. 2020 Nov 12.  doi: 10.1002/ajh.26047.

Key clinical point: Personalized treatment selection according to the LEukemia Artificial intelligence Program (LEAP) recommendations for patients with chronic myeloid leukemia in chronic phase (CML-CP) is associated with better likelihood of survival.

Major finding: The LEAP CML-CP recommendation was associated with an improved overall survival  (P less than 001).

Study details: A cohort of CML-CP patients was randomly assigned to training/validation (n = 504) and test cohorts (n = 126). The training/validation cohort was used to develop the LEAP CML-CP model using 101 variables at diagnosis. The test cohort was then applied to the LEAP CML-CP model and an optimum tyrosine kinase inhibitor therapy was selected for each patient.

Disclosures: The study was supported by the University of Texas MD Anderson Cancer Center Support Grant from the National Institutes of Health, the National Institutes of Health/National Cancer Institute under award, the University of Texas MD Anderson MDS/AML Moon Shot, and Leukemia Texas. K Sasaki, EJ Jabbour, F Ravandi, M Konopleva, G Garcia-Manero, JE Cortes,  C DiNardo reported relationships with various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Sasaki K et al. Am J Hematol. 2020 Nov 12.  doi: 10.1002/ajh.26047.

Key clinical point: There is a decline in renal function among patients with chronic myeloid leukaemia (CML) treated with tyrosine kinase inhibitors (TKIs).

Major finding: There was a significant reduction between the first and final recorded estimated glomerular filtration rate across all patients, declining by a mean of -12 mL/minute/1.73m² over the 10 years of measurement.

Study details: The data come from a retrospective analysis of 50 patients with CML treated with TKI therapy for at least 2 years.

Disclosures: No information on funding was available. The presenting author R Hinton declared no conflicts of interest. The second author S Arami reported relationships with various pharmaceutical companies.

Source: Hinton R et al. Poster. Abstract 053. BSH 2020. 2020 Nov 9-14.

Key clinical point: There is a decline in renal function among patients with chronic myeloid leukaemia (CML) treated with tyrosine kinase inhibitors (TKIs).

Major finding: There was a significant reduction between the first and final recorded estimated glomerular filtration rate across all patients, declining by a mean of -12 mL/minute/1.73m² over the 10 years of measurement.

Study details: The data come from a retrospective analysis of 50 patients with CML treated with TKI therapy for at least 2 years.

Disclosures: No information on funding was available. The presenting author R Hinton declared no conflicts of interest. The second author S Arami reported relationships with various pharmaceutical companies.

Source: Hinton R et al. Poster. Abstract 053. BSH 2020. 2020 Nov 9-14.

Key clinical point: There is a decline in renal function among patients with chronic myeloid leukaemia (CML) treated with tyrosine kinase inhibitors (TKIs).

Major finding: There was a significant reduction between the first and final recorded estimated glomerular filtration rate across all patients, declining by a mean of -12 mL/minute/1.73m² over the 10 years of measurement.

Study details: The data come from a retrospective analysis of 50 patients with CML treated with TKI therapy for at least 2 years.

Disclosures: No information on funding was available. The presenting author R Hinton declared no conflicts of interest. The second author S Arami reported relationships with various pharmaceutical companies.

Source: Hinton R et al. Poster. Abstract 053. BSH 2020. 2020 Nov 9-14.

Key clinical point: This analysis of more than 400 conceptions revealed that the rate of malformations was 2.5% in offsprings of fathers who did not discontinue tyrosine kinase inhibitors (TKIs) before conception, comparable to that measured in the general population.

Major finding: A total of 428 pregnancies from 374 fathers conceived without treatment discontinuation, 400 of which (93.5%) ended up in a live birth. Malformation was reported in 10 offsprings (2.5% of total live births): 6 with imatinib (1.9% of 313 live births), 2 with nilotinib (7.7% of 26 live births), 1 with dasatinib (2.3% of 43 live births), and none with bosutinib (0% of 12 live births).

Study details: A systematic review of 27 nonoverlapping cohorts of patients or case studies.

Disclosures: Study costs were covered by the Economic Development and Innovation Operative Programme Grant; Human Resources Development Operational Programme Grants; and the New National Excellence Programme, Ministry of Human Capacities. The authors declared no conflicts of interest.

Source: Szakács Z et al. PLoS One. 2020 Dec 3. doi: 10.1371/journal.pone.0243045.

Key clinical point: This analysis of more than 400 conceptions revealed that the rate of malformations was 2.5% in offsprings of fathers who did not discontinue tyrosine kinase inhibitors (TKIs) before conception, comparable to that measured in the general population.

Major finding: A total of 428 pregnancies from 374 fathers conceived without treatment discontinuation, 400 of which (93.5%) ended up in a live birth. Malformation was reported in 10 offsprings (2.5% of total live births): 6 with imatinib (1.9% of 313 live births), 2 with nilotinib (7.7% of 26 live births), 1 with dasatinib (2.3% of 43 live births), and none with bosutinib (0% of 12 live births).

Study details: A systematic review of 27 nonoverlapping cohorts of patients or case studies.

Disclosures: Study costs were covered by the Economic Development and Innovation Operative Programme Grant; Human Resources Development Operational Programme Grants; and the New National Excellence Programme, Ministry of Human Capacities. The authors declared no conflicts of interest.

Source: Szakács Z et al. PLoS One. 2020 Dec 3. doi: 10.1371/journal.pone.0243045.

Key clinical point: This analysis of more than 400 conceptions revealed that the rate of malformations was 2.5% in offsprings of fathers who did not discontinue tyrosine kinase inhibitors (TKIs) before conception, comparable to that measured in the general population.

Major finding: A total of 428 pregnancies from 374 fathers conceived without treatment discontinuation, 400 of which (93.5%) ended up in a live birth. Malformation was reported in 10 offsprings (2.5% of total live births): 6 with imatinib (1.9% of 313 live births), 2 with nilotinib (7.7% of 26 live births), 1 with dasatinib (2.3% of 43 live births), and none with bosutinib (0% of 12 live births).

Study details: A systematic review of 27 nonoverlapping cohorts of patients or case studies.

Disclosures: Study costs were covered by the Economic Development and Innovation Operative Programme Grant; Human Resources Development Operational Programme Grants; and the New National Excellence Programme, Ministry of Human Capacities. The authors declared no conflicts of interest.

Source: Szakács Z et al. PLoS One. 2020 Dec 3. doi: 10.1371/journal.pone.0243045.

Key clinical point: In patients with chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) discontinuation seems safe and feasible and is associated with improvements in patient-reported outcomes (PROs).

Major finding: Overall, 65.5% of patients stayed in major molecular response loss, 60.8% achieved treatment-free remission (TFR), and 34.5% had molecular recurrence (MRec). Detectable BCR-ABL1 by real-time quantitative polymerase chain reaction (PCR) or droplet digital PCR at the time of TKI discontinuation was associated with a greater risk of MRec. In patients who had reached TFR at 12 months, TKI discontinuation was associated with improvements in patient-reported fatigue, diarrhea, depression, and sleep disturbance.

Study details: In this prospective single-group nonrandomized LAST study, MRec and PROs after TKI discontinuation for 172 patients with CML in chronic phase (median age, 60 years) from 14 U.S. sites were evaluated. Included patients had well-controlled disease while treated with imatinib, dasatinib, nilotinib, or bosutinib.

Disclosures: This research was supported by a grant from the U.S. National Cancer Institute. The presenting author reported receiving personal fees from Novartis, Bristol Myers Squibb, and Takeda and research support from Novartis and Takeda.

Source: Atallah E et al. JAMA Oncol. 2020 Nov 12. doi: 10.1001/jamaoncol.2020.5774.

Key clinical point: In patients with chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) discontinuation seems safe and feasible and is associated with improvements in patient-reported outcomes (PROs).

Major finding: Overall, 65.5% of patients stayed in major molecular response loss, 60.8% achieved treatment-free remission (TFR), and 34.5% had molecular recurrence (MRec). Detectable BCR-ABL1 by real-time quantitative polymerase chain reaction (PCR) or droplet digital PCR at the time of TKI discontinuation was associated with a greater risk of MRec. In patients who had reached TFR at 12 months, TKI discontinuation was associated with improvements in patient-reported fatigue, diarrhea, depression, and sleep disturbance.

Study details: In this prospective single-group nonrandomized LAST study, MRec and PROs after TKI discontinuation for 172 patients with CML in chronic phase (median age, 60 years) from 14 U.S. sites were evaluated. Included patients had well-controlled disease while treated with imatinib, dasatinib, nilotinib, or bosutinib.

Disclosures: This research was supported by a grant from the U.S. National Cancer Institute. The presenting author reported receiving personal fees from Novartis, Bristol Myers Squibb, and Takeda and research support from Novartis and Takeda.

Source: Atallah E et al. JAMA Oncol. 2020 Nov 12. doi: 10.1001/jamaoncol.2020.5774.

Key clinical point: In patients with chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) discontinuation seems safe and feasible and is associated with improvements in patient-reported outcomes (PROs).

Major finding: Overall, 65.5% of patients stayed in major molecular response loss, 60.8% achieved treatment-free remission (TFR), and 34.5% had molecular recurrence (MRec). Detectable BCR-ABL1 by real-time quantitative polymerase chain reaction (PCR) or droplet digital PCR at the time of TKI discontinuation was associated with a greater risk of MRec. In patients who had reached TFR at 12 months, TKI discontinuation was associated with improvements in patient-reported fatigue, diarrhea, depression, and sleep disturbance.

Study details: In this prospective single-group nonrandomized LAST study, MRec and PROs after TKI discontinuation for 172 patients with CML in chronic phase (median age, 60 years) from 14 U.S. sites were evaluated. Included patients had well-controlled disease while treated with imatinib, dasatinib, nilotinib, or bosutinib.

Disclosures: This research was supported by a grant from the U.S. National Cancer Institute. The presenting author reported receiving personal fees from Novartis, Bristol Myers Squibb, and Takeda and research support from Novartis and Takeda.

Source: Atallah E et al. JAMA Oncol. 2020 Nov 12. doi: 10.1001/jamaoncol.2020.5774.

Key clinical point: Asciminib, a first-in-class STAMP inhibitor, may be a new treatment option for patients with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with 2 or more tyrosine kinase inhibitors.

Major finding: Major molecular response rate at 24 weeks was 25.5% with asciminib and 13.2% with bosutinib (BOS). The between-arm common treatment difference after adjustment for major cytogenetic response status at baseline was 12.2% (2-sided P = .029). Patients treated with asciminib were also twice as likely to achieve a deep molecular response. Grade 3 or greater adverse events were reported in 50.6% and 60.5% of patients receiving asciminib and BOS, respectively.

Study details: In this phase 3 ASCEMBL trial, 233 patients with CML-CP previously treated with 2 or more TKIs were randomly assigned (2:1) to receive asciminib 40 mg twice daily or BOS 500 mg once daily (median follow-up duration, 14.9 months).

Disclosures: The study is sponsored by Novartis. Some of the investigators reported ties with pharmaceutical companies, including Novartis.

Source: Hochhaus A et al. ASH Annual Meeting and Exposition 2020. Abstract LBA-4.

Key clinical point: Asciminib, a first-in-class STAMP inhibitor, may be a new treatment option for patients with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with 2 or more tyrosine kinase inhibitors.

Major finding: Major molecular response rate at 24 weeks was 25.5% with asciminib and 13.2% with bosutinib (BOS). The between-arm common treatment difference after adjustment for major cytogenetic response status at baseline was 12.2% (2-sided P = .029). Patients treated with asciminib were also twice as likely to achieve a deep molecular response. Grade 3 or greater adverse events were reported in 50.6% and 60.5% of patients receiving asciminib and BOS, respectively.

Study details: In this phase 3 ASCEMBL trial, 233 patients with CML-CP previously treated with 2 or more TKIs were randomly assigned (2:1) to receive asciminib 40 mg twice daily or BOS 500 mg once daily (median follow-up duration, 14.9 months).

Disclosures: The study is sponsored by Novartis. Some of the investigators reported ties with pharmaceutical companies, including Novartis.

Source: Hochhaus A et al. ASH Annual Meeting and Exposition 2020. Abstract LBA-4.

Key clinical point: Asciminib, a first-in-class STAMP inhibitor, may be a new treatment option for patients with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with 2 or more tyrosine kinase inhibitors.

Major finding: Major molecular response rate at 24 weeks was 25.5% with asciminib and 13.2% with bosutinib (BOS). The between-arm common treatment difference after adjustment for major cytogenetic response status at baseline was 12.2% (2-sided P = .029). Patients treated with asciminib were also twice as likely to achieve a deep molecular response. Grade 3 or greater adverse events were reported in 50.6% and 60.5% of patients receiving asciminib and BOS, respectively.

Study details: In this phase 3 ASCEMBL trial, 233 patients with CML-CP previously treated with 2 or more TKIs were randomly assigned (2:1) to receive asciminib 40 mg twice daily or BOS 500 mg once daily (median follow-up duration, 14.9 months).

Disclosures: The study is sponsored by Novartis. Some of the investigators reported ties with pharmaceutical companies, including Novartis.

Source: Hochhaus A et al. ASH Annual Meeting and Exposition 2020. Abstract LBA-4.

The investigational drug asciminib (being developed by Novartis) may become the new kid on the block for the treatment of chronic phase chronic myeloid leukemia (CMP-CP) for patients who have relapsed on or are refractory to at least two prior tyrosine kinase inhibitors (TKIs).

New results from the ASCEMBL study (NCT03106779) show that patients who received asciminib, which works differently from currently approved therapies for CML-CP, achieved better responses, compared with bosutinib (Bosulif) as third-line therapy.

“The ASCEMBL study opens a new chapter for CML, proving comparatively superior efficacy and excellent safety for a new class of ABL inhibitors,” coinvestigator Michael J. Mauro, MD, from Memorial Sloan Kettering Cancer Center, New York, said in an interview.

The trial was presented as a late-breaking abstract at the annual meeting of the American Society of Hematology.

Asciminib is a first-of-a-kind STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that works differently from currently approved TKIs, which are adenosine triphosphate (ATP)-–competitive ABL inhibitors.

Five TKIs have been approved by the Food and Drug Administration to treat CML: imatinib (Gleevec; generics), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib, and ponatinib (Iclusig).

All of them inhibit BCR/ABL tyrosine kinase by binding to the ATP-binding pocket.

Most patients with TKI resistant disease develop mutations in the ATP-binding pocket, explained Michael Jay Styler, MD, associate professor at Fox Chase–Temple University Hospital bone marrow transplant program, Fox Chase Cancer Center, Philadelphia.

By inactivating the protein through binding outside the ATP site, asciminib is a novel BCR-ABL inhibitor and may be a superior alternative to further traditional TKIs. “This agent promises to be an important addition to our treatment armamentarium for CML,” Dr. Styler said in an interview.

Another expert agreed. “Although we have many excellent therapies for CML, having a new medication that targets BCR-ABL in a novel way is still welcome to help us better care for CML patients,” Gabriela S. Hobbs, MD, said in an interview. Dr. Hobbs is the clinical director of leukemia services at Boston’s Mass General Cancer Center.

Patients in this study had previously been receiving at least two different types of TKIs. “The responses looked very encouraging for this group of heavily pretreated patients. Although CML patients do very well on current therapies, those that don’t get a response with TKI remain a difficult clinical challenge,” Dr. Hobbs said.

“This is the first study comparing asciminib to a TKI directly (in this case bosutinib) and it showed safety as well as preliminary evidence of efficacy. I look forward to seeing additional studies with this promising drug and to have a new drug to add to the CML arsenal,” she added.
 

Identifying patients who will benefit from asciminib

Patients with CML are currently sequenced through more than one second-generation TKI, Dr. Mauro commented. “If imatinib and a second-generation TKI have not served a patient well, only bosutinib has been studied in the third line and comparatively in the ASCEMBL study.” Asciminib was shown to be superior and could offer a clear alternative to ponatinib, which would be the other choice and is typically given even later after sequencing all other available options.

Dr. Hobbs agreed. “This is a challenging group of patients to manage as their options are limited. Ponatinib is often the drug of choice in these scenarios, as well as bone marrow transplant.”

Asciminib is not approved yet, but both Dr. Mauro and Dr. Hobbs are hopeful it will be by early next year, and that initial approval is likely in patients with CML-CP after several (two or three) lines of therapy. They also agreed that it may be effective (alone or in combination) in treating patients with T315I-mutation CML, which is a particularly challenging disease.

Senior study author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II in Jena, Germany, who presented the data at the meeting, noted new trials to test the efficacy of asciminib alone or in combination in earlier lines of therapy are ongoing and include the investigator-initiated FASCINATION study (first-line asciminib in combination) in Germany (NCT03906292).
 

ASCEMBL study details

ASCEMBL is a phase 3 study in which patients with CML who had received at least two previous TKIs were randomized to asciminib (n = 157) 40 mg twice daily or bosutinib (n = 76) 500 mg once daily. In a protocol amendment, patients with documented failure on bosutinib were allowed to switch to asciminib.

The main reason for discontinuing the last TKI therapy was lack of efficacy in approximately two-thirds of patients. More patients in the asciminib than the bosutinib group received two prior lines of therapy (52% vs. 40%); the others had received three or more prior lines of therapy.

Median follow-up for the data cutoff was 14.9 months.

Dr. Hochhaus reported that treatment discontinuation was lower in patients receiving asciminib than bosutinib (38% vs. 70%) and was mostly due to lack of efficacy (21% vs. 32%) or adverse events (5% vs. 21%).

The study met its primary endpoint: major molecular response (MMR) was approximately twice as high with asciminib than bosutinib at 24 weeks (25.5% vs. 13.2%; P = .029). Treatment effect for MMR was 12.2%. Median duration of exposure to asciminib was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.

“Consistent treatment effect was seen across all subgroups of patients, and MMR rates were consistently high for patients on asciminib across all prior lines of therapy,” Dr. Hochhaus reported.

The probability of achieving MMR at 24 weeks was higher for patients receiving asciminib (25% vs. 11.9%) and started at week 12, he noted. Complete cytogenetic response was also higher for patients receiving asciminib (40.8% vs. 24.2%).

The occurrence of grade 3 or higher adverse events was lower with asciminib than bosutinib (51% vs. 61%). Thrombocytopenia and neutropenia were more common with asciminib and gastrointestinal events were more common with bosutinib. Arterial occlusion events were reported in five patients receiving asciminib and one patient receiving bosutinib. Most of these patients had prior exposure to imatinib, nilotinib, and/or dasatinib.

Dr. Mauro, a coinvestigator of the phase 3 study, also treated patients with the drug in the phase 1 study. “I feel asciminib has proven to be very well tolerated, with rare to absent cases of intolerance,” he said. Cardiovascular and cardiopulmonary adverse events are exceedingly rare as well.

Longer follow-up of the ASCEMBL study and continued follow-up of the myriad of groups from the phase 1 trial (T315I-positive patients treated with higher-dose asciminib, combination therapy with imatinib/nilotinib/dasatinib plus asciminib, and others) will be essential to settle any questions regarding selective adverse events of interest such as vascular occlusion, Dr. Mauro noted.

Dr. Hochhaus has reported receiving research funding from Novartis, Incyte, Pfizer, and Bristol-Myers Squibb. Dr. Hobbs has reported serving on advisory boards for Novartis. Dr. Mauro has reported financial relationships with Bristol-Myers Squibb, Novartis, Takeda, Pfizer, and Sun Pharma/SPARC.

A version of this article first appeared on Medscape.com.

The investigational drug asciminib (being developed by Novartis) may become the new kid on the block for the treatment of chronic phase chronic myeloid leukemia (CMP-CP) for patients who have relapsed on or are refractory to at least two prior tyrosine kinase inhibitors (TKIs).

New results from the ASCEMBL study (NCT03106779) show that patients who received asciminib, which works differently from currently approved therapies for CML-CP, achieved better responses, compared with bosutinib (Bosulif) as third-line therapy.

“The ASCEMBL study opens a new chapter for CML, proving comparatively superior efficacy and excellent safety for a new class of ABL inhibitors,” coinvestigator Michael J. Mauro, MD, from Memorial Sloan Kettering Cancer Center, New York, said in an interview.

The trial was presented as a late-breaking abstract at the annual meeting of the American Society of Hematology.

Asciminib is a first-of-a-kind STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that works differently from currently approved TKIs, which are adenosine triphosphate (ATP)-–competitive ABL inhibitors.

Five TKIs have been approved by the Food and Drug Administration to treat CML: imatinib (Gleevec; generics), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib, and ponatinib (Iclusig).

All of them inhibit BCR/ABL tyrosine kinase by binding to the ATP-binding pocket.

Most patients with TKI resistant disease develop mutations in the ATP-binding pocket, explained Michael Jay Styler, MD, associate professor at Fox Chase–Temple University Hospital bone marrow transplant program, Fox Chase Cancer Center, Philadelphia.

By inactivating the protein through binding outside the ATP site, asciminib is a novel BCR-ABL inhibitor and may be a superior alternative to further traditional TKIs. “This agent promises to be an important addition to our treatment armamentarium for CML,” Dr. Styler said in an interview.

Another expert agreed. “Although we have many excellent therapies for CML, having a new medication that targets BCR-ABL in a novel way is still welcome to help us better care for CML patients,” Gabriela S. Hobbs, MD, said in an interview. Dr. Hobbs is the clinical director of leukemia services at Boston’s Mass General Cancer Center.

Patients in this study had previously been receiving at least two different types of TKIs. “The responses looked very encouraging for this group of heavily pretreated patients. Although CML patients do very well on current therapies, those that don’t get a response with TKI remain a difficult clinical challenge,” Dr. Hobbs said.

“This is the first study comparing asciminib to a TKI directly (in this case bosutinib) and it showed safety as well as preliminary evidence of efficacy. I look forward to seeing additional studies with this promising drug and to have a new drug to add to the CML arsenal,” she added.
 

Identifying patients who will benefit from asciminib

Patients with CML are currently sequenced through more than one second-generation TKI, Dr. Mauro commented. “If imatinib and a second-generation TKI have not served a patient well, only bosutinib has been studied in the third line and comparatively in the ASCEMBL study.” Asciminib was shown to be superior and could offer a clear alternative to ponatinib, which would be the other choice and is typically given even later after sequencing all other available options.

Dr. Hobbs agreed. “This is a challenging group of patients to manage as their options are limited. Ponatinib is often the drug of choice in these scenarios, as well as bone marrow transplant.”

Asciminib is not approved yet, but both Dr. Mauro and Dr. Hobbs are hopeful it will be by early next year, and that initial approval is likely in patients with CML-CP after several (two or three) lines of therapy. They also agreed that it may be effective (alone or in combination) in treating patients with T315I-mutation CML, which is a particularly challenging disease.

Senior study author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II in Jena, Germany, who presented the data at the meeting, noted new trials to test the efficacy of asciminib alone or in combination in earlier lines of therapy are ongoing and include the investigator-initiated FASCINATION study (first-line asciminib in combination) in Germany (NCT03906292).
 

ASCEMBL study details

ASCEMBL is a phase 3 study in which patients with CML who had received at least two previous TKIs were randomized to asciminib (n = 157) 40 mg twice daily or bosutinib (n = 76) 500 mg once daily. In a protocol amendment, patients with documented failure on bosutinib were allowed to switch to asciminib.

The main reason for discontinuing the last TKI therapy was lack of efficacy in approximately two-thirds of patients. More patients in the asciminib than the bosutinib group received two prior lines of therapy (52% vs. 40%); the others had received three or more prior lines of therapy.

Median follow-up for the data cutoff was 14.9 months.

Dr. Hochhaus reported that treatment discontinuation was lower in patients receiving asciminib than bosutinib (38% vs. 70%) and was mostly due to lack of efficacy (21% vs. 32%) or adverse events (5% vs. 21%).

The study met its primary endpoint: major molecular response (MMR) was approximately twice as high with asciminib than bosutinib at 24 weeks (25.5% vs. 13.2%; P = .029). Treatment effect for MMR was 12.2%. Median duration of exposure to asciminib was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.

“Consistent treatment effect was seen across all subgroups of patients, and MMR rates were consistently high for patients on asciminib across all prior lines of therapy,” Dr. Hochhaus reported.

The probability of achieving MMR at 24 weeks was higher for patients receiving asciminib (25% vs. 11.9%) and started at week 12, he noted. Complete cytogenetic response was also higher for patients receiving asciminib (40.8% vs. 24.2%).

The occurrence of grade 3 or higher adverse events was lower with asciminib than bosutinib (51% vs. 61%). Thrombocytopenia and neutropenia were more common with asciminib and gastrointestinal events were more common with bosutinib. Arterial occlusion events were reported in five patients receiving asciminib and one patient receiving bosutinib. Most of these patients had prior exposure to imatinib, nilotinib, and/or dasatinib.

Dr. Mauro, a coinvestigator of the phase 3 study, also treated patients with the drug in the phase 1 study. “I feel asciminib has proven to be very well tolerated, with rare to absent cases of intolerance,” he said. Cardiovascular and cardiopulmonary adverse events are exceedingly rare as well.

Longer follow-up of the ASCEMBL study and continued follow-up of the myriad of groups from the phase 1 trial (T315I-positive patients treated with higher-dose asciminib, combination therapy with imatinib/nilotinib/dasatinib plus asciminib, and others) will be essential to settle any questions regarding selective adverse events of interest such as vascular occlusion, Dr. Mauro noted.

Dr. Hochhaus has reported receiving research funding from Novartis, Incyte, Pfizer, and Bristol-Myers Squibb. Dr. Hobbs has reported serving on advisory boards for Novartis. Dr. Mauro has reported financial relationships with Bristol-Myers Squibb, Novartis, Takeda, Pfizer, and Sun Pharma/SPARC.

A version of this article first appeared on Medscape.com.

The investigational drug asciminib (being developed by Novartis) may become the new kid on the block for the treatment of chronic phase chronic myeloid leukemia (CMP-CP) for patients who have relapsed on or are refractory to at least two prior tyrosine kinase inhibitors (TKIs).

New results from the ASCEMBL study (NCT03106779) show that patients who received asciminib, which works differently from currently approved therapies for CML-CP, achieved better responses, compared with bosutinib (Bosulif) as third-line therapy.

“The ASCEMBL study opens a new chapter for CML, proving comparatively superior efficacy and excellent safety for a new class of ABL inhibitors,” coinvestigator Michael J. Mauro, MD, from Memorial Sloan Kettering Cancer Center, New York, said in an interview.

The trial was presented as a late-breaking abstract at the annual meeting of the American Society of Hematology.

Asciminib is a first-of-a-kind STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that works differently from currently approved TKIs, which are adenosine triphosphate (ATP)-–competitive ABL inhibitors.

Five TKIs have been approved by the Food and Drug Administration to treat CML: imatinib (Gleevec; generics), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib, and ponatinib (Iclusig).

All of them inhibit BCR/ABL tyrosine kinase by binding to the ATP-binding pocket.

Most patients with TKI resistant disease develop mutations in the ATP-binding pocket, explained Michael Jay Styler, MD, associate professor at Fox Chase–Temple University Hospital bone marrow transplant program, Fox Chase Cancer Center, Philadelphia.

By inactivating the protein through binding outside the ATP site, asciminib is a novel BCR-ABL inhibitor and may be a superior alternative to further traditional TKIs. “This agent promises to be an important addition to our treatment armamentarium for CML,” Dr. Styler said in an interview.

Another expert agreed. “Although we have many excellent therapies for CML, having a new medication that targets BCR-ABL in a novel way is still welcome to help us better care for CML patients,” Gabriela S. Hobbs, MD, said in an interview. Dr. Hobbs is the clinical director of leukemia services at Boston’s Mass General Cancer Center.

Patients in this study had previously been receiving at least two different types of TKIs. “The responses looked very encouraging for this group of heavily pretreated patients. Although CML patients do very well on current therapies, those that don’t get a response with TKI remain a difficult clinical challenge,” Dr. Hobbs said.

“This is the first study comparing asciminib to a TKI directly (in this case bosutinib) and it showed safety as well as preliminary evidence of efficacy. I look forward to seeing additional studies with this promising drug and to have a new drug to add to the CML arsenal,” she added.
 

Identifying patients who will benefit from asciminib

Patients with CML are currently sequenced through more than one second-generation TKI, Dr. Mauro commented. “If imatinib and a second-generation TKI have not served a patient well, only bosutinib has been studied in the third line and comparatively in the ASCEMBL study.” Asciminib was shown to be superior and could offer a clear alternative to ponatinib, which would be the other choice and is typically given even later after sequencing all other available options.

Dr. Hobbs agreed. “This is a challenging group of patients to manage as their options are limited. Ponatinib is often the drug of choice in these scenarios, as well as bone marrow transplant.”

Asciminib is not approved yet, but both Dr. Mauro and Dr. Hobbs are hopeful it will be by early next year, and that initial approval is likely in patients with CML-CP after several (two or three) lines of therapy. They also agreed that it may be effective (alone or in combination) in treating patients with T315I-mutation CML, which is a particularly challenging disease.

Senior study author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II in Jena, Germany, who presented the data at the meeting, noted new trials to test the efficacy of asciminib alone or in combination in earlier lines of therapy are ongoing and include the investigator-initiated FASCINATION study (first-line asciminib in combination) in Germany (NCT03906292).
 

ASCEMBL study details

ASCEMBL is a phase 3 study in which patients with CML who had received at least two previous TKIs were randomized to asciminib (n = 157) 40 mg twice daily or bosutinib (n = 76) 500 mg once daily. In a protocol amendment, patients with documented failure on bosutinib were allowed to switch to asciminib.

The main reason for discontinuing the last TKI therapy was lack of efficacy in approximately two-thirds of patients. More patients in the asciminib than the bosutinib group received two prior lines of therapy (52% vs. 40%); the others had received three or more prior lines of therapy.

Median follow-up for the data cutoff was 14.9 months.

Dr. Hochhaus reported that treatment discontinuation was lower in patients receiving asciminib than bosutinib (38% vs. 70%) and was mostly due to lack of efficacy (21% vs. 32%) or adverse events (5% vs. 21%).

The study met its primary endpoint: major molecular response (MMR) was approximately twice as high with asciminib than bosutinib at 24 weeks (25.5% vs. 13.2%; P = .029). Treatment effect for MMR was 12.2%. Median duration of exposure to asciminib was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.

“Consistent treatment effect was seen across all subgroups of patients, and MMR rates were consistently high for patients on asciminib across all prior lines of therapy,” Dr. Hochhaus reported.

The probability of achieving MMR at 24 weeks was higher for patients receiving asciminib (25% vs. 11.9%) and started at week 12, he noted. Complete cytogenetic response was also higher for patients receiving asciminib (40.8% vs. 24.2%).

The occurrence of grade 3 or higher adverse events was lower with asciminib than bosutinib (51% vs. 61%). Thrombocytopenia and neutropenia were more common with asciminib and gastrointestinal events were more common with bosutinib. Arterial occlusion events were reported in five patients receiving asciminib and one patient receiving bosutinib. Most of these patients had prior exposure to imatinib, nilotinib, and/or dasatinib.

Dr. Mauro, a coinvestigator of the phase 3 study, also treated patients with the drug in the phase 1 study. “I feel asciminib has proven to be very well tolerated, with rare to absent cases of intolerance,” he said. Cardiovascular and cardiopulmonary adverse events are exceedingly rare as well.

Longer follow-up of the ASCEMBL study and continued follow-up of the myriad of groups from the phase 1 trial (T315I-positive patients treated with higher-dose asciminib, combination therapy with imatinib/nilotinib/dasatinib plus asciminib, and others) will be essential to settle any questions regarding selective adverse events of interest such as vascular occlusion, Dr. Mauro noted.

Dr. Hochhaus has reported receiving research funding from Novartis, Incyte, Pfizer, and Bristol-Myers Squibb. Dr. Hobbs has reported serving on advisory boards for Novartis. Dr. Mauro has reported financial relationships with Bristol-Myers Squibb, Novartis, Takeda, Pfizer, and Sun Pharma/SPARC.

A version of this article first appeared on Medscape.com.

An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.

The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).

Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.

The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.

The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.

The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).

The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
 

Impact on treatment

The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).

Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).

Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.

On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.

Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.

“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.

“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

Frontline Medical News

Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.

Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.

Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
 

Telehealth, meetings, and trials

The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).

Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).

While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.

Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.

Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.

He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”

This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.

SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.

An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.

The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).

Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.

The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.

The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.

The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).

The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
 

Impact on treatment

The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).

Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).

Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.

On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.

Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.

“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.

“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

Frontline Medical News

Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.

Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.

Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
 

Telehealth, meetings, and trials

The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).

Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).

While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.

Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.

Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.

He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”

This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.

SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.

An international survey provides new insights into how COVID-19 has affected, and may continue to affect, the field of oncology.

The survey showed that “COVID-19 has had a major impact on the organization of patient care, on the well-being of caregivers, on continued medical education, and on clinical trial activities in oncology,” stated Guy Jerusalem, MD, PhD, of Centre Hospitalier Universitaire de Liège (Belgium).

Dr. Jerusalem presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

The survey was distributed by 20 oncologists from 10 of the countries most affected by COVID-19. Responses were obtained from 109 oncologists representing centers in 18 countries. The responses were recorded between June 17 and July 14, 2020.

The survey consisted of 95 items intended to evaluate the impact of COVID-19 on the organization of oncologic care. Questions encompassed the capacity and service offered at each center, the magnitude of COVID-19–based care interruptions and the reasons for them, the ensuing challenges faced, interventions implemented, and the estimated harms to patients during the pandemic.

The 109 oncologists surveyed had a median of 20 years of oncology experience. A majority of respondents were men (61.5%), and the median age was 48.5 years.

The respondents had worked predominantly (62.4%) at academic hospitals, with 29.6% at community hospitals. Most respondents worked at general hospitals with an oncology unit (66.1%) rather than a specialized separate cancer center (32.1%).

The most common specialty was breast cancer (60.6%), followed by gastrointestinal cancer (10.1%), urogenital cancer (9.2%), and lung cancer (8.3%).
 

Impact on treatment

The treatment modalities affected by the pandemic – through cancellations or delays in more than 10% of patients – included surgery (in 34% of centers), chemotherapy (22%), radiotherapy (13.7%), checkpoint inhibitor therapy (9.1%), monoclonal antibodies (9%), and oral targeted therapy (3.7%).

Among oncologists treating breast cancer, cancellations/delays in more than 10% of patients were reported for everolimus (18%), CDK4/6 inhibitors (8.9%), and endocrine therapy (2.2%).

Overall, 34.8% of respondents reported increased use of granulocyte colony–stimulating factor, and 6.4% reported increased use of erythropoietin.

On the other hand, 11.1% of respondents reported a decrease in the use of double immunotherapy, and 21.9% reported decreased use of corticosteroids.

Not only can the immunosuppressive effects of steroid use increase infection risks, Dr. Jerusalem noted, fever suppression can lead to a delayed diagnosis of COVID-19.

“To circumvent potential higher infection risks or greater disease severity, we use lower doses of steroids, but this is not based on studies,” he said.

“Previous exposure to steroids or being on steroids at the time of COVID-19 infection is a detrimental factor for complications and mortality,” commented ESMO President Solange Peters, MD, PhD, of Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland.

Frontline Medical News

Dr. Peters noted that the observation was based on lung cancer registry findings. Furthermore, because data from smaller outbreaks of other coronavirus infections suggested worse prognosis and increased mortality, steroid use was already feared in the very early days of the COVID-19 pandemic.

Lastly, earlier cessation of palliative treatment was observed in 32.1% of centers, and 64.2% of respondents agreed that undertreatment because of COVID-19 is a major concern.

Dr. Jerusalem noted that the survey data do not explain the early cessation of palliative treatment. “I suspect that many patients died at home rather than alone in institutions because it was the only way they could die with their families around them.”
 

Telehealth, meetings, and trials

The survey also revealed rationales for the use of teleconsultation, including follow-up (94.5%), oral therapy (92.7%), immunotherapy (57.8%), and chemotherapy (55%).

Most respondents reported more frequent use of virtual meetings for continuing medical education (94%), oncologic team meetings (92%), and tumor boards (82%).

While about 82% of respondents said they were likely to continue the use of telemedicine, 45% said virtual conferences are not an acceptable alternative to live international conferences such as ESMO, Dr. Jerusalem said.

Finally, nearly three-quarters of respondents (72.5%) said all clinical trial activities are or will soon be activated, or never stopped, at their centers. On the other hand, 27.5% of respondents reported that their centers had major protocol violations or deviations, and 37% of respondents said they expect significant reductions in clinical trial activities this year.

Dr. Jerusalem concluded that COVID-19 is having a major, long-term impact on the organization of patient care, caregivers, continued medical education, and clinical trial activities in oncology.

He cautioned that “the risk of a delayed diagnosis of new cancers and economic consequences of COVID-19 on access to health care and cancer treatments have to be carefully evaluated.”

This research was funded by Fondation Léon Fredericq. Dr. Jerusalem disclosed relationships with Novartis, Roche, Lilly, Pfizer, Amgen, Bristol-Myers Squibb, AstraZeneca, Daiichi Sankyo, AbbVie, MedImmune, and Merck. Dr. Peters disclosed relationships with AbbVie, Amgen, AstraZeneca, and many other companies.

SOURCE: Jerusalem G et al. ESMO 2020, Abstract LBA76.

The rate of reduction in BCR-ABL1 value during the first 3 months of tyrosine kinase inhibitor therapy for chronic myeloid leukemia (CML) independently predicts the likelihood of sustained treatment-free remission (TFR) in eligible patients, a recent study shows.

The findings, along with the 10-year outcomes data from the phase 3 ENESTnd trial reported in 2019, can help with complex TFR decision-making, lead author Timothy P. Hughes, MD, said at the Society of Hematologic Oncology virtual meeting.

In 115 chronic-phase CML patients who were eligible and attempted TFR and had at least 12 months of follow-up, the probability of sustained TFR, defined as major molecular response off tyrosine kinase inhibitor therapy for 12 continuous months, was 55%. The time to halving of the BCR-ABL1 value after the start of therapy was the strongest independent predictor of success. Sustained TFR occurred in 80% of those in the first quartile of response time (halving time of less than 9.4 days), compared with 4% of those in the last quartile (halving time of more than 21.9 days), said Dr. Hughes of the South Australian Health and Medical Research Institute, Adelaide.

The model assumes molecular response of 4.5 status duration for 3 years – not just achievement of MR4.5.

“So that’s the other variable in this equation,’ he said.

The findings, which were published online Sept. 1 in Blood, were validated in an independent dataset.

Dr. Hughes and colleagues concluded that the data “support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.”

As an example of how the findings, along with those from ENESTnd, can help with TFR decision-making, Dr. Hughes presented a case involving a 59-year-old man with chronic-phase CML diagnosed 5 years prior with intermediate EUTOS long-term survival score (ELTS) and Sokal scores and a low Framingham Risk Score at diagnosis.

The patient was treated with frontline nilotinib at a standard dose of 300 mg twice daily and he responded well, achieving an MR4 molecular response after 18 months, and MR4.5 score at 2.5 years, which was maintained at 5 years.

“That’s a BCR-ABL level of less than 0.01% on the International Scale,” he said, noting that the patient’s BCR-ABL level started at 290% and had “a very, very steep fall to 0.26% at 3 months.”
 

Cardiovascular risk a factor

The patient was interested in attempting TFR when eligible, but had some vascular toxicity risks; he was being treated for hypertension and hypercholesterolemia and also had a family history of coronary artery disease.

Hypercholesterolemia is a recognized effect of nilotinib therapy, but both where being treated and were under control, Dr. Hughes noted.

The patient’s Framingham Risk Score had increased from 9 (low risk) to 16 (intermediate risk).

In determining whether to attempt TFR and closely monitor the patient or delay the attempt and perhaps either change to imatinib therapy or reduce the nilotinib dose, Dr. Hughes said it was important to consider the cardiovascular event risks as elucidated in ENESTnd.

It was hoped that the increased cardiovascular event risk demonstrated in years 0-5 of the study would diminish in the later years, but the 10-year finding actually showed persistent risk with nilotinib treatment: In years 0-5, 7.2%, 11.9% and 1.8% of patients in study arms receiving nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib 400 mg once daily, respectively, experienced a cardiovascular event. In years 5-10, the corresponding rates were 9.3%, 11.9%, and 1.8%.

“I think it’s an important message that the risk is there, at about the same rate, in the second 5 years,” said Dr. Hughes, the first author of the study.

The ENESTnd data also show how the Framingham Risk Score, which is based mainly on age, cholesterol levels, blood pressure, smoking history, and diabetes history, is associated with cardiovascular event rates in the treatment arms.

Patients with a low Framingham score who were receiving nilotinib had no greater risk of a cardiovascular event than did those receiving nilotinib during years 0-5.

“I think that makes it an attractive option in patients where you’re focusing on early achievement of deep molecular response and eligibility for treatment-free remission,” he said, adding that it’s a different story for those with intermediate or high Framingham scores, who have “ a really quite substantial” risk in the first 5 years.

The 5- to 10-year ENESTnd data, however, show that this lack of risk in low Framingham scores did not hold true. Even in those with a low-risk Framingham score, the overall 10-year event rate was 7.3% with nilotinib versus 1.1% with imatinib.

“This is an important message that it’s probably not appropriate to assume that your patient with low Framingham Risk Score at diagnosis is not having a higher risk of cardiovascular events in the period after 5 years out to 10 years,” Dr. Hughes said.

Of note, the case patient was considered eligible for TFR under all of the mandatory requirements of both the 2020 European LeukemiaNET recommendations and the National Comprehensive Cancer Network 2020 guideline for CML, which have slight differences but are “generally in accord.”

Based on those recommendations, the patient would be “eligible and probably recommended,” for TFR, he said.

The 10-year ENESTnd findings and the findings by Dr. Hughes and colleagues with respect to the tempo of early tyrosine kinase inhibitor response provide further confirmation of the patient’s eligibility.

“I would feel very happy to say to this patient: ‘You’ve got an excellent chance of achieving treatment-free remission today; going on with therapy is probably not in your interest given the risk of a cardiovascular event, so I’d recommend stopping,’ ” he said. “If the patient was not keen to stop, then I’d recommend switching to imatinib, because I don’t think we’re getting any great benefit from pushing on with nilotinib if the plan is not to attempt treatment-free remission.”

However, if the patient preferred another year of treatment before attempting TFR, it might be worth considering reducing the dose or switching to low-dose dasatinib, he noted, concluding that “the vascular risk profile and the prospect of treatment-free remission need to be carefully considered in every patient, particularly patients on second-generation drugs, before deciding whether to recommend treatment-free remission or extending therapy longer and whether it’s appropriate to just reduce the dose or switch.”

Dr. Hughes has received grant or research support and honoraria from Novartis and Bristol-Myers Squibb, and has been a paid consultant and advisory committee or review panel member for both companies.

[email protected]

The rate of reduction in BCR-ABL1 value during the first 3 months of tyrosine kinase inhibitor therapy for chronic myeloid leukemia (CML) independently predicts the likelihood of sustained treatment-free remission (TFR) in eligible patients, a recent study shows.

The findings, along with the 10-year outcomes data from the phase 3 ENESTnd trial reported in 2019, can help with complex TFR decision-making, lead author Timothy P. Hughes, MD, said at the Society of Hematologic Oncology virtual meeting.

In 115 chronic-phase CML patients who were eligible and attempted TFR and had at least 12 months of follow-up, the probability of sustained TFR, defined as major molecular response off tyrosine kinase inhibitor therapy for 12 continuous months, was 55%. The time to halving of the BCR-ABL1 value after the start of therapy was the strongest independent predictor of success. Sustained TFR occurred in 80% of those in the first quartile of response time (halving time of less than 9.4 days), compared with 4% of those in the last quartile (halving time of more than 21.9 days), said Dr. Hughes of the South Australian Health and Medical Research Institute, Adelaide.

The model assumes molecular response of 4.5 status duration for 3 years – not just achievement of MR4.5.

“So that’s the other variable in this equation,’ he said.

The findings, which were published online Sept. 1 in Blood, were validated in an independent dataset.

Dr. Hughes and colleagues concluded that the data “support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.”

As an example of how the findings, along with those from ENESTnd, can help with TFR decision-making, Dr. Hughes presented a case involving a 59-year-old man with chronic-phase CML diagnosed 5 years prior with intermediate EUTOS long-term survival score (ELTS) and Sokal scores and a low Framingham Risk Score at diagnosis.

The patient was treated with frontline nilotinib at a standard dose of 300 mg twice daily and he responded well, achieving an MR4 molecular response after 18 months, and MR4.5 score at 2.5 years, which was maintained at 5 years.

“That’s a BCR-ABL level of less than 0.01% on the International Scale,” he said, noting that the patient’s BCR-ABL level started at 290% and had “a very, very steep fall to 0.26% at 3 months.”
 

Cardiovascular risk a factor

The patient was interested in attempting TFR when eligible, but had some vascular toxicity risks; he was being treated for hypertension and hypercholesterolemia and also had a family history of coronary artery disease.

Hypercholesterolemia is a recognized effect of nilotinib therapy, but both where being treated and were under control, Dr. Hughes noted.

The patient’s Framingham Risk Score had increased from 9 (low risk) to 16 (intermediate risk).

In determining whether to attempt TFR and closely monitor the patient or delay the attempt and perhaps either change to imatinib therapy or reduce the nilotinib dose, Dr. Hughes said it was important to consider the cardiovascular event risks as elucidated in ENESTnd.

It was hoped that the increased cardiovascular event risk demonstrated in years 0-5 of the study would diminish in the later years, but the 10-year finding actually showed persistent risk with nilotinib treatment: In years 0-5, 7.2%, 11.9% and 1.8% of patients in study arms receiving nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib 400 mg once daily, respectively, experienced a cardiovascular event. In years 5-10, the corresponding rates were 9.3%, 11.9%, and 1.8%.

“I think it’s an important message that the risk is there, at about the same rate, in the second 5 years,” said Dr. Hughes, the first author of the study.

The ENESTnd data also show how the Framingham Risk Score, which is based mainly on age, cholesterol levels, blood pressure, smoking history, and diabetes history, is associated with cardiovascular event rates in the treatment arms.

Patients with a low Framingham score who were receiving nilotinib had no greater risk of a cardiovascular event than did those receiving nilotinib during years 0-5.

“I think that makes it an attractive option in patients where you’re focusing on early achievement of deep molecular response and eligibility for treatment-free remission,” he said, adding that it’s a different story for those with intermediate or high Framingham scores, who have “ a really quite substantial” risk in the first 5 years.

The 5- to 10-year ENESTnd data, however, show that this lack of risk in low Framingham scores did not hold true. Even in those with a low-risk Framingham score, the overall 10-year event rate was 7.3% with nilotinib versus 1.1% with imatinib.

“This is an important message that it’s probably not appropriate to assume that your patient with low Framingham Risk Score at diagnosis is not having a higher risk of cardiovascular events in the period after 5 years out to 10 years,” Dr. Hughes said.

Of note, the case patient was considered eligible for TFR under all of the mandatory requirements of both the 2020 European LeukemiaNET recommendations and the National Comprehensive Cancer Network 2020 guideline for CML, which have slight differences but are “generally in accord.”

Based on those recommendations, the patient would be “eligible and probably recommended,” for TFR, he said.

The 10-year ENESTnd findings and the findings by Dr. Hughes and colleagues with respect to the tempo of early tyrosine kinase inhibitor response provide further confirmation of the patient’s eligibility.

“I would feel very happy to say to this patient: ‘You’ve got an excellent chance of achieving treatment-free remission today; going on with therapy is probably not in your interest given the risk of a cardiovascular event, so I’d recommend stopping,’ ” he said. “If the patient was not keen to stop, then I’d recommend switching to imatinib, because I don’t think we’re getting any great benefit from pushing on with nilotinib if the plan is not to attempt treatment-free remission.”

However, if the patient preferred another year of treatment before attempting TFR, it might be worth considering reducing the dose or switching to low-dose dasatinib, he noted, concluding that “the vascular risk profile and the prospect of treatment-free remission need to be carefully considered in every patient, particularly patients on second-generation drugs, before deciding whether to recommend treatment-free remission or extending therapy longer and whether it’s appropriate to just reduce the dose or switch.”

Dr. Hughes has received grant or research support and honoraria from Novartis and Bristol-Myers Squibb, and has been a paid consultant and advisory committee or review panel member for both companies.

[email protected]

The rate of reduction in BCR-ABL1 value during the first 3 months of tyrosine kinase inhibitor therapy for chronic myeloid leukemia (CML) independently predicts the likelihood of sustained treatment-free remission (TFR) in eligible patients, a recent study shows.

The findings, along with the 10-year outcomes data from the phase 3 ENESTnd trial reported in 2019, can help with complex TFR decision-making, lead author Timothy P. Hughes, MD, said at the Society of Hematologic Oncology virtual meeting.

In 115 chronic-phase CML patients who were eligible and attempted TFR and had at least 12 months of follow-up, the probability of sustained TFR, defined as major molecular response off tyrosine kinase inhibitor therapy for 12 continuous months, was 55%. The time to halving of the BCR-ABL1 value after the start of therapy was the strongest independent predictor of success. Sustained TFR occurred in 80% of those in the first quartile of response time (halving time of less than 9.4 days), compared with 4% of those in the last quartile (halving time of more than 21.9 days), said Dr. Hughes of the South Australian Health and Medical Research Institute, Adelaide.

The model assumes molecular response of 4.5 status duration for 3 years – not just achievement of MR4.5.

“So that’s the other variable in this equation,’ he said.

The findings, which were published online Sept. 1 in Blood, were validated in an independent dataset.

Dr. Hughes and colleagues concluded that the data “support the critical importance of the initial kinetics of BCR-ABL1 decline for long-term outcomes.”

As an example of how the findings, along with those from ENESTnd, can help with TFR decision-making, Dr. Hughes presented a case involving a 59-year-old man with chronic-phase CML diagnosed 5 years prior with intermediate EUTOS long-term survival score (ELTS) and Sokal scores and a low Framingham Risk Score at diagnosis.

The patient was treated with frontline nilotinib at a standard dose of 300 mg twice daily and he responded well, achieving an MR4 molecular response after 18 months, and MR4.5 score at 2.5 years, which was maintained at 5 years.

“That’s a BCR-ABL level of less than 0.01% on the International Scale,” he said, noting that the patient’s BCR-ABL level started at 290% and had “a very, very steep fall to 0.26% at 3 months.”
 

Cardiovascular risk a factor

The patient was interested in attempting TFR when eligible, but had some vascular toxicity risks; he was being treated for hypertension and hypercholesterolemia and also had a family history of coronary artery disease.

Hypercholesterolemia is a recognized effect of nilotinib therapy, but both where being treated and were under control, Dr. Hughes noted.

The patient’s Framingham Risk Score had increased from 9 (low risk) to 16 (intermediate risk).

In determining whether to attempt TFR and closely monitor the patient or delay the attempt and perhaps either change to imatinib therapy or reduce the nilotinib dose, Dr. Hughes said it was important to consider the cardiovascular event risks as elucidated in ENESTnd.

It was hoped that the increased cardiovascular event risk demonstrated in years 0-5 of the study would diminish in the later years, but the 10-year finding actually showed persistent risk with nilotinib treatment: In years 0-5, 7.2%, 11.9% and 1.8% of patients in study arms receiving nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, and imatinib 400 mg once daily, respectively, experienced a cardiovascular event. In years 5-10, the corresponding rates were 9.3%, 11.9%, and 1.8%.

“I think it’s an important message that the risk is there, at about the same rate, in the second 5 years,” said Dr. Hughes, the first author of the study.

The ENESTnd data also show how the Framingham Risk Score, which is based mainly on age, cholesterol levels, blood pressure, smoking history, and diabetes history, is associated with cardiovascular event rates in the treatment arms.

Patients with a low Framingham score who were receiving nilotinib had no greater risk of a cardiovascular event than did those receiving nilotinib during years 0-5.

“I think that makes it an attractive option in patients where you’re focusing on early achievement of deep molecular response and eligibility for treatment-free remission,” he said, adding that it’s a different story for those with intermediate or high Framingham scores, who have “ a really quite substantial” risk in the first 5 years.

The 5- to 10-year ENESTnd data, however, show that this lack of risk in low Framingham scores did not hold true. Even in those with a low-risk Framingham score, the overall 10-year event rate was 7.3% with nilotinib versus 1.1% with imatinib.

“This is an important message that it’s probably not appropriate to assume that your patient with low Framingham Risk Score at diagnosis is not having a higher risk of cardiovascular events in the period after 5 years out to 10 years,” Dr. Hughes said.

Of note, the case patient was considered eligible for TFR under all of the mandatory requirements of both the 2020 European LeukemiaNET recommendations and the National Comprehensive Cancer Network 2020 guideline for CML, which have slight differences but are “generally in accord.”

Based on those recommendations, the patient would be “eligible and probably recommended,” for TFR, he said.

The 10-year ENESTnd findings and the findings by Dr. Hughes and colleagues with respect to the tempo of early tyrosine kinase inhibitor response provide further confirmation of the patient’s eligibility.

“I would feel very happy to say to this patient: ‘You’ve got an excellent chance of achieving treatment-free remission today; going on with therapy is probably not in your interest given the risk of a cardiovascular event, so I’d recommend stopping,’ ” he said. “If the patient was not keen to stop, then I’d recommend switching to imatinib, because I don’t think we’re getting any great benefit from pushing on with nilotinib if the plan is not to attempt treatment-free remission.”

However, if the patient preferred another year of treatment before attempting TFR, it might be worth considering reducing the dose or switching to low-dose dasatinib, he noted, concluding that “the vascular risk profile and the prospect of treatment-free remission need to be carefully considered in every patient, particularly patients on second-generation drugs, before deciding whether to recommend treatment-free remission or extending therapy longer and whether it’s appropriate to just reduce the dose or switch.”

Dr. Hughes has received grant or research support and honoraria from Novartis and Bristol-Myers Squibb, and has been a paid consultant and advisory committee or review panel member for both companies.

[email protected]

Most patients with chronic myeloid leukemia (CML) have a normal life expectancy thanks to dramatic improvements in treatments and outcomes over the past few decades, but new treatment approaches are needed for the subset who fail to respond or who develop resistance to existing treatments, according to Jorge Cortes, MD, director of the Georgia Cancer Center, Augusta.

Several novel tyrosine kinase inhibitors (TKIs) and combination therapies show promise in early studies, he said at the Society of Hematologic Oncology virtual meeting.
 

Asciminib

The allosteric inhibitor asciminib (ABL-001), for example, has completed phase 1/2 trials evaluating its use as a single agent and in combination with other therapies in the first-line setting, and a pivotal phase 3 study comparing it with bosutinib in the third-line setting is underway, Dr. Cortes said.

The rate of major cytogenetic response (MCyr) to asciminib in heavily pretreated patients in a phase 1/2 study published the New England Journal of Medicine was “very good” at 77%.

“And almost half [48%] of the patients had a major molecular response by 12 months,” he said, noting that even after excluding those who had a prior response but were enrolled because they couldn’t tolerate prior treatments, the MCyr and major molecular response (MMR) rates were 60% and 36%, respectively.

Asciminib also showed activity in patients with T315I mutations: The MCyr rate was 55% and the MMR rate at 12 months was 24%.

“Now, it is important to recognize that the doses that are required for inhibition – for getting these responses in [patients with] T315I – are higher than we need for the patients that do not have T315I, so it needs higher concentrations in vitro and it needs higher doses in vivo,” he said.

Also of note, the response rates were good both in those with two or fewer prior lines of therapy and in those with three or more (12-month MMR rates were 47% and 34%, respectively). For the latter, that’s “a very good rate, even though we’re only talking about 12 months of therapy,” Dr. Cortes said.

“And even in the patients who had been resistant or intolerant to ponatinib, 40% achieved a major molecular response, so very good results regardless of the number or type of tyrosine kinase inhibitors the patient had received, ” he added. The numbers in the group with T315I mutations are small, so further exploration is needed in subsequent studies, he noted.

The emergence of resistance is a concern with asciminib, but in a xenograft model, combining it with nilotinib appeared to prevent resistance. Therefore, the combination of asciminib and various TKIs has been explored in the clinic.

In a phase 1 study of asciminib and imatinib presented by Dr. Cortes at the European Hematology Association meeting in 2019, the complete cytogenetic response and MMR rates at 48 weeks were 50% and 42%, respectively.

“Now, this is a different type of population – perhaps a little more heavily pretreated than the ones who received single-agent asciminib, but it does show the potential for synergy, and importantly it was not associated with increased toxicity,” he said.
 

PF-114

Another agent in development is PF-114, a third-generation BCR-ABL inhibitor. It is a structural analogue of ponatinib that is modified to avoid inhibiting the VEGFR receptor in an effort to prevent “arterial occlusive and particularly hypertension, adverse events that we see with ponatinib,” he said.

In a phase 1 study of 51 patients with CML who failed at least two prior TKIs or had T315I mutation, the MCyr rate was 50% and the MMR rate was 36%. The drug was very well tolerated: The dose-limiting toxicity was skin toxicity involving psoriasiform lesions, which were manageable, he noted.

“Importantly ... there was no cardiovascular toxicity,” he added.

Those findings were presented at ASH 2018. The drug is now moving to a phase 2 study.
 

HQP1351 (GZD824)

The orally active, small-molecule BCR-ABL inhibitor HQP1351 is a third-generation TKI with activity against a broad spectrum of BCR-ABL mutations.

A phase 1 study of patients who were resistant to prior TKIs is complete, and results presented at ASH 2019 showed that most patients (67%) had only one or two prior therapies and 63% had T315I mutation. Response rates were better in the patients with T315I mutations (MCyr, 78% vs. 34%; MMR, 52% vs. 15% in 101 chronic phase patients).

The treatment was well tolerated, with grade 3 toxicity involving only hypertriglyceridemia, pyrexia, and proteinuria. No arterial occlusive events were reported.
 

K0706

K0706 is a selective inhibitor of BCR-ABL1 designed to inhibit enzymatic activity of BCR-ABL. The agent was efficacious and well tolerated with limited off-target activity in preclinical models. It can inhibit wild-type and mutant forms of BCR-ABL, but does not have activity against T315I.

Results of a phase 1 study presented at ASH in 2019 by Dr. Cortes showed that all the patients who received a dose of 174 mg or greater achieved or maintained a cytogenetic response at 6 months, and 50% achieved or maintained an MMR.

“This is a very good response rate in this heavily pretreated population,” he said.

Patients who received prior ponatinib had a somewhat lower response, but still, nearly 45% achieved an MCyr.

“So very good response rates, no arterial occlusive events, and phase 2 studies will be starting at the dose of 174 mg,” he said.
 

Additional combinations

As for combining TKIs with other agents, efforts are underway around the world to find ways to eradicate minimal residual disease. Examples include TKIs and imatinib, TKIs and azacitidine, and asciminib plus another TKI, to name a few.

One study from Germany showed that adding interferon leads to earlier achievement of MMR, but ultimately the responses were similar, Dr. Cortes said.

Adding venetoclax has shown some activity in the preclinical setting, and studies of that combination will be starting soon in the clinic, he noted.
 

Implications

The current survival probability in CML patients is 92% when considering CML-related deaths (68% when considering all-cause mortality), compared with 8% in the 1980s and 35%-43% in the early 1990s.

But the current benefits don’t extend to all patients, Dr. Cortes said.

“There are patients who actually end up having worse prognosis than we would expect,” he said, explaining that some CML-related deaths are attributable to lack of access to therapy and good care, but some are related to true poor prognosis, often caused by resistance or inability to tolerate treatments.

In fact, data from studies of various treatments show that almost 40% of patients on dasatinib or nilotinib change therapy by 5 years, and by 10 years, half of those randomized to nilotinib have changed therapy.

“So it is not uncommon that patients have to change therapy for one reason or another,” he said, adding that, as resistance persists through additional treatment options, the prognosis worsens significantly.

“It is important that we have new therapeutic options to be able to help these patients who are going to be in need of additional therapies,” he said.

Dr. Cortes has received grant or research support from Novartis, Pfizer, Takeda, and Sun Pharma, and he is a paid consultant for Pfizer, Novartis, and Takeda.

[email protected]

Most patients with chronic myeloid leukemia (CML) have a normal life expectancy thanks to dramatic improvements in treatments and outcomes over the past few decades, but new treatment approaches are needed for the subset who fail to respond or who develop resistance to existing treatments, according to Jorge Cortes, MD, director of the Georgia Cancer Center, Augusta.

Several novel tyrosine kinase inhibitors (TKIs) and combination therapies show promise in early studies, he said at the Society of Hematologic Oncology virtual meeting.
 

Asciminib

The allosteric inhibitor asciminib (ABL-001), for example, has completed phase 1/2 trials evaluating its use as a single agent and in combination with other therapies in the first-line setting, and a pivotal phase 3 study comparing it with bosutinib in the third-line setting is underway, Dr. Cortes said.

The rate of major cytogenetic response (MCyr) to asciminib in heavily pretreated patients in a phase 1/2 study published the New England Journal of Medicine was “very good” at 77%.

“And almost half [48%] of the patients had a major molecular response by 12 months,” he said, noting that even after excluding those who had a prior response but were enrolled because they couldn’t tolerate prior treatments, the MCyr and major molecular response (MMR) rates were 60% and 36%, respectively.

Asciminib also showed activity in patients with T315I mutations: The MCyr rate was 55% and the MMR rate at 12 months was 24%.

“Now, it is important to recognize that the doses that are required for inhibition – for getting these responses in [patients with] T315I – are higher than we need for the patients that do not have T315I, so it needs higher concentrations in vitro and it needs higher doses in vivo,” he said.

Also of note, the response rates were good both in those with two or fewer prior lines of therapy and in those with three or more (12-month MMR rates were 47% and 34%, respectively). For the latter, that’s “a very good rate, even though we’re only talking about 12 months of therapy,” Dr. Cortes said.

“And even in the patients who had been resistant or intolerant to ponatinib, 40% achieved a major molecular response, so very good results regardless of the number or type of tyrosine kinase inhibitors the patient had received, ” he added. The numbers in the group with T315I mutations are small, so further exploration is needed in subsequent studies, he noted.

The emergence of resistance is a concern with asciminib, but in a xenograft model, combining it with nilotinib appeared to prevent resistance. Therefore, the combination of asciminib and various TKIs has been explored in the clinic.

In a phase 1 study of asciminib and imatinib presented by Dr. Cortes at the European Hematology Association meeting in 2019, the complete cytogenetic response and MMR rates at 48 weeks were 50% and 42%, respectively.

“Now, this is a different type of population – perhaps a little more heavily pretreated than the ones who received single-agent asciminib, but it does show the potential for synergy, and importantly it was not associated with increased toxicity,” he said.
 

PF-114

Another agent in development is PF-114, a third-generation BCR-ABL inhibitor. It is a structural analogue of ponatinib that is modified to avoid inhibiting the VEGFR receptor in an effort to prevent “arterial occlusive and particularly hypertension, adverse events that we see with ponatinib,” he said.

In a phase 1 study of 51 patients with CML who failed at least two prior TKIs or had T315I mutation, the MCyr rate was 50% and the MMR rate was 36%. The drug was very well tolerated: The dose-limiting toxicity was skin toxicity involving psoriasiform lesions, which were manageable, he noted.

“Importantly ... there was no cardiovascular toxicity,” he added.

Those findings were presented at ASH 2018. The drug is now moving to a phase 2 study.
 

HQP1351 (GZD824)

The orally active, small-molecule BCR-ABL inhibitor HQP1351 is a third-generation TKI with activity against a broad spectrum of BCR-ABL mutations.

A phase 1 study of patients who were resistant to prior TKIs is complete, and results presented at ASH 2019 showed that most patients (67%) had only one or two prior therapies and 63% had T315I mutation. Response rates were better in the patients with T315I mutations (MCyr, 78% vs. 34%; MMR, 52% vs. 15% in 101 chronic phase patients).

The treatment was well tolerated, with grade 3 toxicity involving only hypertriglyceridemia, pyrexia, and proteinuria. No arterial occlusive events were reported.
 

K0706

K0706 is a selective inhibitor of BCR-ABL1 designed to inhibit enzymatic activity of BCR-ABL. The agent was efficacious and well tolerated with limited off-target activity in preclinical models. It can inhibit wild-type and mutant forms of BCR-ABL, but does not have activity against T315I.

Results of a phase 1 study presented at ASH in 2019 by Dr. Cortes showed that all the patients who received a dose of 174 mg or greater achieved or maintained a cytogenetic response at 6 months, and 50% achieved or maintained an MMR.

“This is a very good response rate in this heavily pretreated population,” he said.

Patients who received prior ponatinib had a somewhat lower response, but still, nearly 45% achieved an MCyr.

“So very good response rates, no arterial occlusive events, and phase 2 studies will be starting at the dose of 174 mg,” he said.
 

Additional combinations

As for combining TKIs with other agents, efforts are underway around the world to find ways to eradicate minimal residual disease. Examples include TKIs and imatinib, TKIs and azacitidine, and asciminib plus another TKI, to name a few.

One study from Germany showed that adding interferon leads to earlier achievement of MMR, but ultimately the responses were similar, Dr. Cortes said.

Adding venetoclax has shown some activity in the preclinical setting, and studies of that combination will be starting soon in the clinic, he noted.
 

Implications

The current survival probability in CML patients is 92% when considering CML-related deaths (68% when considering all-cause mortality), compared with 8% in the 1980s and 35%-43% in the early 1990s.

But the current benefits don’t extend to all patients, Dr. Cortes said.

“There are patients who actually end up having worse prognosis than we would expect,” he said, explaining that some CML-related deaths are attributable to lack of access to therapy and good care, but some are related to true poor prognosis, often caused by resistance or inability to tolerate treatments.

In fact, data from studies of various treatments show that almost 40% of patients on dasatinib or nilotinib change therapy by 5 years, and by 10 years, half of those randomized to nilotinib have changed therapy.

“So it is not uncommon that patients have to change therapy for one reason or another,” he said, adding that, as resistance persists through additional treatment options, the prognosis worsens significantly.

“It is important that we have new therapeutic options to be able to help these patients who are going to be in need of additional therapies,” he said.

Dr. Cortes has received grant or research support from Novartis, Pfizer, Takeda, and Sun Pharma, and he is a paid consultant for Pfizer, Novartis, and Takeda.

[email protected]

Most patients with chronic myeloid leukemia (CML) have a normal life expectancy thanks to dramatic improvements in treatments and outcomes over the past few decades, but new treatment approaches are needed for the subset who fail to respond or who develop resistance to existing treatments, according to Jorge Cortes, MD, director of the Georgia Cancer Center, Augusta.

Several novel tyrosine kinase inhibitors (TKIs) and combination therapies show promise in early studies, he said at the Society of Hematologic Oncology virtual meeting.
 

Asciminib

The allosteric inhibitor asciminib (ABL-001), for example, has completed phase 1/2 trials evaluating its use as a single agent and in combination with other therapies in the first-line setting, and a pivotal phase 3 study comparing it with bosutinib in the third-line setting is underway, Dr. Cortes said.

The rate of major cytogenetic response (MCyr) to asciminib in heavily pretreated patients in a phase 1/2 study published the New England Journal of Medicine was “very good” at 77%.

“And almost half [48%] of the patients had a major molecular response by 12 months,” he said, noting that even after excluding those who had a prior response but were enrolled because they couldn’t tolerate prior treatments, the MCyr and major molecular response (MMR) rates were 60% and 36%, respectively.

Asciminib also showed activity in patients with T315I mutations: The MCyr rate was 55% and the MMR rate at 12 months was 24%.

“Now, it is important to recognize that the doses that are required for inhibition – for getting these responses in [patients with] T315I – are higher than we need for the patients that do not have T315I, so it needs higher concentrations in vitro and it needs higher doses in vivo,” he said.

Also of note, the response rates were good both in those with two or fewer prior lines of therapy and in those with three or more (12-month MMR rates were 47% and 34%, respectively). For the latter, that’s “a very good rate, even though we’re only talking about 12 months of therapy,” Dr. Cortes said.

“And even in the patients who had been resistant or intolerant to ponatinib, 40% achieved a major molecular response, so very good results regardless of the number or type of tyrosine kinase inhibitors the patient had received, ” he added. The numbers in the group with T315I mutations are small, so further exploration is needed in subsequent studies, he noted.

The emergence of resistance is a concern with asciminib, but in a xenograft model, combining it with nilotinib appeared to prevent resistance. Therefore, the combination of asciminib and various TKIs has been explored in the clinic.

In a phase 1 study of asciminib and imatinib presented by Dr. Cortes at the European Hematology Association meeting in 2019, the complete cytogenetic response and MMR rates at 48 weeks were 50% and 42%, respectively.

“Now, this is a different type of population – perhaps a little more heavily pretreated than the ones who received single-agent asciminib, but it does show the potential for synergy, and importantly it was not associated with increased toxicity,” he said.
 

PF-114

Another agent in development is PF-114, a third-generation BCR-ABL inhibitor. It is a structural analogue of ponatinib that is modified to avoid inhibiting the VEGFR receptor in an effort to prevent “arterial occlusive and particularly hypertension, adverse events that we see with ponatinib,” he said.

In a phase 1 study of 51 patients with CML who failed at least two prior TKIs or had T315I mutation, the MCyr rate was 50% and the MMR rate was 36%. The drug was very well tolerated: The dose-limiting toxicity was skin toxicity involving psoriasiform lesions, which were manageable, he noted.

“Importantly ... there was no cardiovascular toxicity,” he added.

Those findings were presented at ASH 2018. The drug is now moving to a phase 2 study.
 

HQP1351 (GZD824)

The orally active, small-molecule BCR-ABL inhibitor HQP1351 is a third-generation TKI with activity against a broad spectrum of BCR-ABL mutations.

A phase 1 study of patients who were resistant to prior TKIs is complete, and results presented at ASH 2019 showed that most patients (67%) had only one or two prior therapies and 63% had T315I mutation. Response rates were better in the patients with T315I mutations (MCyr, 78% vs. 34%; MMR, 52% vs. 15% in 101 chronic phase patients).

The treatment was well tolerated, with grade 3 toxicity involving only hypertriglyceridemia, pyrexia, and proteinuria. No arterial occlusive events were reported.
 

K0706

K0706 is a selective inhibitor of BCR-ABL1 designed to inhibit enzymatic activity of BCR-ABL. The agent was efficacious and well tolerated with limited off-target activity in preclinical models. It can inhibit wild-type and mutant forms of BCR-ABL, but does not have activity against T315I.

Results of a phase 1 study presented at ASH in 2019 by Dr. Cortes showed that all the patients who received a dose of 174 mg or greater achieved or maintained a cytogenetic response at 6 months, and 50% achieved or maintained an MMR.

“This is a very good response rate in this heavily pretreated population,” he said.

Patients who received prior ponatinib had a somewhat lower response, but still, nearly 45% achieved an MCyr.

“So very good response rates, no arterial occlusive events, and phase 2 studies will be starting at the dose of 174 mg,” he said.
 

Additional combinations

As for combining TKIs with other agents, efforts are underway around the world to find ways to eradicate minimal residual disease. Examples include TKIs and imatinib, TKIs and azacitidine, and asciminib plus another TKI, to name a few.

One study from Germany showed that adding interferon leads to earlier achievement of MMR, but ultimately the responses were similar, Dr. Cortes said.

Adding venetoclax has shown some activity in the preclinical setting, and studies of that combination will be starting soon in the clinic, he noted.
 

Implications

The current survival probability in CML patients is 92% when considering CML-related deaths (68% when considering all-cause mortality), compared with 8% in the 1980s and 35%-43% in the early 1990s.

But the current benefits don’t extend to all patients, Dr. Cortes said.

“There are patients who actually end up having worse prognosis than we would expect,” he said, explaining that some CML-related deaths are attributable to lack of access to therapy and good care, but some are related to true poor prognosis, often caused by resistance or inability to tolerate treatments.

In fact, data from studies of various treatments show that almost 40% of patients on dasatinib or nilotinib change therapy by 5 years, and by 10 years, half of those randomized to nilotinib have changed therapy.

“So it is not uncommon that patients have to change therapy for one reason or another,” he said, adding that, as resistance persists through additional treatment options, the prognosis worsens significantly.

“It is important that we have new therapeutic options to be able to help these patients who are going to be in need of additional therapies,” he said.

Dr. Cortes has received grant or research support from Novartis, Pfizer, Takeda, and Sun Pharma, and he is a paid consultant for Pfizer, Novartis, and Takeda.

[email protected]