CML

Key clinical point: BCR/ABL transcript type B3a2_e14a2 is more common than B2a2_e13a2 in patients with chronic myeloid leukemia (CML) with B3a2_e14a2 being more common in women than men.

Major finding: The overall estimated prevalence was highest for B3a2_e14a2 transcript (54%), followed by B2a2_e13a2 (39%) and dual B2a2_e13a2/B3a2_e14a2 (1.11%) transcripts (all P less than .0001), with B3a2_e14a2 being more prevalent in women vs. men (60.6% vs. 51.1%; P less than .0001).

Study details: Findings are from a meta-analysis of 34 studies that evaluated the prevalence of main BCR/ABL transcript types in patients with CML.

Disclosures: No specific funding source was identified. The authors declared no conflicts of interest.

Source: Ghalesardi OK et al. Leuk Res. 2021 Jan 19. doi: 10.1016/j.leukres.2021.106512.

Key clinical point: BCR/ABL transcript type B3a2_e14a2 is more common than B2a2_e13a2 in patients with chronic myeloid leukemia (CML) with B3a2_e14a2 being more common in women than men.

Major finding: The overall estimated prevalence was highest for B3a2_e14a2 transcript (54%), followed by B2a2_e13a2 (39%) and dual B2a2_e13a2/B3a2_e14a2 (1.11%) transcripts (all P less than .0001), with B3a2_e14a2 being more prevalent in women vs. men (60.6% vs. 51.1%; P less than .0001).

Study details: Findings are from a meta-analysis of 34 studies that evaluated the prevalence of main BCR/ABL transcript types in patients with CML.

Disclosures: No specific funding source was identified. The authors declared no conflicts of interest.

Source: Ghalesardi OK et al. Leuk Res. 2021 Jan 19. doi: 10.1016/j.leukres.2021.106512.

Key clinical point: BCR/ABL transcript type B3a2_e14a2 is more common than B2a2_e13a2 in patients with chronic myeloid leukemia (CML) with B3a2_e14a2 being more common in women than men.

Major finding: The overall estimated prevalence was highest for B3a2_e14a2 transcript (54%), followed by B2a2_e13a2 (39%) and dual B2a2_e13a2/B3a2_e14a2 (1.11%) transcripts (all P less than .0001), with B3a2_e14a2 being more prevalent in women vs. men (60.6% vs. 51.1%; P less than .0001).

Study details: Findings are from a meta-analysis of 34 studies that evaluated the prevalence of main BCR/ABL transcript types in patients with CML.

Disclosures: No specific funding source was identified. The authors declared no conflicts of interest.

Source: Ghalesardi OK et al. Leuk Res. 2021 Jan 19. doi: 10.1016/j.leukres.2021.106512.

Key clinical point: Right ventricular systolic pressure (RVSP) increased significantly following dasatinib therapy in some patients with chronic-phase chronic myeloid leukemia (CML-CP), leading to dasatinib-induced pulmonary arterial hypertension (D-PAH) and consequent therapy discontinuation.

Major finding: During a median of 36.2 months of dasatinib therapy, mean RSVP increased significantly and gradually (P less than .001). Overall, 56 patients had RVSP over 40 mmHg, of which 51.8% of patients were diagnosed with D-PAH with clinical symptoms, all ultimately switching to other tyrosine kinase inhibitors.

Study details: Findings are from an analysis of a cohort of 451 patients with CML-CP who underwent 2D-echocardiography at least once at baseline and/or during dasatinib therapy (mean dose, 85 mg/day) as frontline (n=196) and subsequent line (n=255).

Disclosures: This study was funded by Korea Leukemia Bank. The authors declared no conflicts of interest.

Source: Lee SE et al. Cancer Med. 2021 Feb 15. doi: 10.1002/cam4.3588.

Key clinical point: Right ventricular systolic pressure (RVSP) increased significantly following dasatinib therapy in some patients with chronic-phase chronic myeloid leukemia (CML-CP), leading to dasatinib-induced pulmonary arterial hypertension (D-PAH) and consequent therapy discontinuation.

Major finding: During a median of 36.2 months of dasatinib therapy, mean RSVP increased significantly and gradually (P less than .001). Overall, 56 patients had RVSP over 40 mmHg, of which 51.8% of patients were diagnosed with D-PAH with clinical symptoms, all ultimately switching to other tyrosine kinase inhibitors.

Study details: Findings are from an analysis of a cohort of 451 patients with CML-CP who underwent 2D-echocardiography at least once at baseline and/or during dasatinib therapy (mean dose, 85 mg/day) as frontline (n=196) and subsequent line (n=255).

Disclosures: This study was funded by Korea Leukemia Bank. The authors declared no conflicts of interest.

Source: Lee SE et al. Cancer Med. 2021 Feb 15. doi: 10.1002/cam4.3588.

Key clinical point: Right ventricular systolic pressure (RVSP) increased significantly following dasatinib therapy in some patients with chronic-phase chronic myeloid leukemia (CML-CP), leading to dasatinib-induced pulmonary arterial hypertension (D-PAH) and consequent therapy discontinuation.

Major finding: During a median of 36.2 months of dasatinib therapy, mean RSVP increased significantly and gradually (P less than .001). Overall, 56 patients had RVSP over 40 mmHg, of which 51.8% of patients were diagnosed with D-PAH with clinical symptoms, all ultimately switching to other tyrosine kinase inhibitors.

Study details: Findings are from an analysis of a cohort of 451 patients with CML-CP who underwent 2D-echocardiography at least once at baseline and/or during dasatinib therapy (mean dose, 85 mg/day) as frontline (n=196) and subsequent line (n=255).

Disclosures: This study was funded by Korea Leukemia Bank. The authors declared no conflicts of interest.

Source: Lee SE et al. Cancer Med. 2021 Feb 15. doi: 10.1002/cam4.3588.

Key clinical point: Asciminib is a safe and effective drug in patients with chronic myeloid leukemia (CML) without treatment alternatives in common clinical practice.

Major finding: After a median of 8.8 months on asciminib, the cumulative response rates of complete hematologic response, complete cytogenetic response, and major molecular response were 100%, 66%, and 41%, respectively. Improvement in baseline response and maintenance of baseline response were observed in 55% and 90% of patients, respectively. At last evaluation, 87% of patients remained on asciminib treatment with none discontinuing because of treatment-emergent adverse events.

Study details: Findings are from a retrospective analysis of 31 BCR-ABL1-positive patients with CML treated with asciminib. Patients were heavily treated and switched to asciminib because of intolerance (n=22) or resistance (n=9) to prior tyrosine kinase inhibitors. All patients were treated under the managed-access program by Novartis.

Disclosures: No information on funding was available. Four of the authors including the lead author reported being on advisory committees, receiving funds, and/or speaker honoraria from various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Garcia-Gutiérrez V et al. Blood Cancer J. 2021 Feb 9. doi: 10.1038/s41408-021-00420-8.

Key clinical point: Asciminib is a safe and effective drug in patients with chronic myeloid leukemia (CML) without treatment alternatives in common clinical practice.

Major finding: After a median of 8.8 months on asciminib, the cumulative response rates of complete hematologic response, complete cytogenetic response, and major molecular response were 100%, 66%, and 41%, respectively. Improvement in baseline response and maintenance of baseline response were observed in 55% and 90% of patients, respectively. At last evaluation, 87% of patients remained on asciminib treatment with none discontinuing because of treatment-emergent adverse events.

Study details: Findings are from a retrospective analysis of 31 BCR-ABL1-positive patients with CML treated with asciminib. Patients were heavily treated and switched to asciminib because of intolerance (n=22) or resistance (n=9) to prior tyrosine kinase inhibitors. All patients were treated under the managed-access program by Novartis.

Disclosures: No information on funding was available. Four of the authors including the lead author reported being on advisory committees, receiving funds, and/or speaker honoraria from various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Garcia-Gutiérrez V et al. Blood Cancer J. 2021 Feb 9. doi: 10.1038/s41408-021-00420-8.

Key clinical point: Asciminib is a safe and effective drug in patients with chronic myeloid leukemia (CML) without treatment alternatives in common clinical practice.

Major finding: After a median of 8.8 months on asciminib, the cumulative response rates of complete hematologic response, complete cytogenetic response, and major molecular response were 100%, 66%, and 41%, respectively. Improvement in baseline response and maintenance of baseline response were observed in 55% and 90% of patients, respectively. At last evaluation, 87% of patients remained on asciminib treatment with none discontinuing because of treatment-emergent adverse events.

Study details: Findings are from a retrospective analysis of 31 BCR-ABL1-positive patients with CML treated with asciminib. Patients were heavily treated and switched to asciminib because of intolerance (n=22) or resistance (n=9) to prior tyrosine kinase inhibitors. All patients were treated under the managed-access program by Novartis.

Disclosures: No information on funding was available. Four of the authors including the lead author reported being on advisory committees, receiving funds, and/or speaker honoraria from various pharmaceutical companies. The remaining authors declared no conflicts of interest.

Source: Garcia-Gutiérrez V et al. Blood Cancer J. 2021 Feb 9. doi: 10.1038/s41408-021-00420-8.

Key clinical point: At 2 years, molecular recurrence-free survival (MRFS) after imatinib discontinuation was observed in over half of the patients with chronic phase-chronic myeloid leukemia (CML-CP) with sustained molecular response of 4log (MR4). MR of 4.5log (MR4.5) was associated with a lower risk of relapse.

Major finding: At 24 months, MRFS was 54% (95% CI, 39%-75%). Molecular relapse was observed in 42% of patients. All patients reachieved major molecular response after resuming imatinib. MR4.5 at discontinuation was associated with a lower risk of molecular relapse (odds ratio, 0.32; P = .03).

Study details: Findings are from a prospective study that evaluated treatment-free survival after imatinib discontinuation in 31 patients with CML-CP with sustained MR4 for at least 12 months and treated with first-line imatinib for at least 36 months.

Disclosures: No specific funding was received for this study. The authors declared no conflicts of interest.

Source: Seguro FS et al. Leuk Res. 2021 Jan 21. doi: 10.1016/j.leukres.2021.106516.

Key clinical point: At 2 years, molecular recurrence-free survival (MRFS) after imatinib discontinuation was observed in over half of the patients with chronic phase-chronic myeloid leukemia (CML-CP) with sustained molecular response of 4log (MR4). MR of 4.5log (MR4.5) was associated with a lower risk of relapse.

Major finding: At 24 months, MRFS was 54% (95% CI, 39%-75%). Molecular relapse was observed in 42% of patients. All patients reachieved major molecular response after resuming imatinib. MR4.5 at discontinuation was associated with a lower risk of molecular relapse (odds ratio, 0.32; P = .03).

Study details: Findings are from a prospective study that evaluated treatment-free survival after imatinib discontinuation in 31 patients with CML-CP with sustained MR4 for at least 12 months and treated with first-line imatinib for at least 36 months.

Disclosures: No specific funding was received for this study. The authors declared no conflicts of interest.

Source: Seguro FS et al. Leuk Res. 2021 Jan 21. doi: 10.1016/j.leukres.2021.106516.

Key clinical point: At 2 years, molecular recurrence-free survival (MRFS) after imatinib discontinuation was observed in over half of the patients with chronic phase-chronic myeloid leukemia (CML-CP) with sustained molecular response of 4log (MR4). MR of 4.5log (MR4.5) was associated with a lower risk of relapse.

Major finding: At 24 months, MRFS was 54% (95% CI, 39%-75%). Molecular relapse was observed in 42% of patients. All patients reachieved major molecular response after resuming imatinib. MR4.5 at discontinuation was associated with a lower risk of molecular relapse (odds ratio, 0.32; P = .03).

Study details: Findings are from a prospective study that evaluated treatment-free survival after imatinib discontinuation in 31 patients with CML-CP with sustained MR4 for at least 12 months and treated with first-line imatinib for at least 36 months.

Disclosures: No specific funding was received for this study. The authors declared no conflicts of interest.

Source: Seguro FS et al. Leuk Res. 2021 Jan 21. doi: 10.1016/j.leukres.2021.106516.

Key clinical point: Asian patients with chronic myeloid leukemia in chronic phase (CML-CP) with a higher dasatinib dose adjusted for body weight (dose/BW) experienced a higher risk of dose-limiting toxicities (DLTs). The fixed starting dose of dasatinib 100 mg may not be optimal in Asian patients.

Major finding: By 36 months after initiation of dasatinib 100 mg once daily (OD) as frontline therapy, 55.9% of patients experienced at least 1 DLT. Higher dasatinib dose/BW was associated with a higher risk of DLT occurrence (odds ratio, 4.84; P = .03).

Study details: This study assessed the effect of a fixed starting dose of dasatinib (100 mg OD) in 102 Asian patients with newly diagnosed CML-CP.

Disclosures: This study was funded by the National Research Foundation of Korea, the Foundation of Pharmacy Education and Research, and the Research Institutes of Pharmaceutical Sciences (Seoul National University). The lead author had no disclosures. DW Kim reported the use of clinical data collected from a separate research study (funded by Bristol-Myers Squibb) for this study.

Source: Shin H et al. Clin Lymphoma Myeloma Leuk. 2021 Feb 1 doi: 10.1016/j.clml.2021.01.020.

Key clinical point: Asian patients with chronic myeloid leukemia in chronic phase (CML-CP) with a higher dasatinib dose adjusted for body weight (dose/BW) experienced a higher risk of dose-limiting toxicities (DLTs). The fixed starting dose of dasatinib 100 mg may not be optimal in Asian patients.

Major finding: By 36 months after initiation of dasatinib 100 mg once daily (OD) as frontline therapy, 55.9% of patients experienced at least 1 DLT. Higher dasatinib dose/BW was associated with a higher risk of DLT occurrence (odds ratio, 4.84; P = .03).

Study details: This study assessed the effect of a fixed starting dose of dasatinib (100 mg OD) in 102 Asian patients with newly diagnosed CML-CP.

Disclosures: This study was funded by the National Research Foundation of Korea, the Foundation of Pharmacy Education and Research, and the Research Institutes of Pharmaceutical Sciences (Seoul National University). The lead author had no disclosures. DW Kim reported the use of clinical data collected from a separate research study (funded by Bristol-Myers Squibb) for this study.

Source: Shin H et al. Clin Lymphoma Myeloma Leuk. 2021 Feb 1 doi: 10.1016/j.clml.2021.01.020.

Key clinical point: Asian patients with chronic myeloid leukemia in chronic phase (CML-CP) with a higher dasatinib dose adjusted for body weight (dose/BW) experienced a higher risk of dose-limiting toxicities (DLTs). The fixed starting dose of dasatinib 100 mg may not be optimal in Asian patients.

Major finding: By 36 months after initiation of dasatinib 100 mg once daily (OD) as frontline therapy, 55.9% of patients experienced at least 1 DLT. Higher dasatinib dose/BW was associated with a higher risk of DLT occurrence (odds ratio, 4.84; P = .03).

Study details: This study assessed the effect of a fixed starting dose of dasatinib (100 mg OD) in 102 Asian patients with newly diagnosed CML-CP.

Disclosures: This study was funded by the National Research Foundation of Korea, the Foundation of Pharmacy Education and Research, and the Research Institutes of Pharmaceutical Sciences (Seoul National University). The lead author had no disclosures. DW Kim reported the use of clinical data collected from a separate research study (funded by Bristol-Myers Squibb) for this study.

Source: Shin H et al. Clin Lymphoma Myeloma Leuk. 2021 Feb 1 doi: 10.1016/j.clml.2021.01.020.

Key clinical point: Late relapses do occur after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic-phase chronic myeloid leukemia (CML-CP) in treatment-free remission (TFR) at 36 months, with molecular response (MR) status at 36 months being highly predictive of subsequent molecular relapse.

Major finding: During a follow-up of 72 months, 10.8% of patients in TFR at 36 months lost major MR. Not being in MR4 at 36 months of TKI discontinuation was associated with an 85% higher risk of molecular relapse during the subsequent 3 years.

Study details: Findings are from the 6-year follow-up (AFTER-SKI) of 111 patients with CML-CP who were in TFR at 36 months after TKI discontinuation from the EURO-SKI trial.

Disclosures: This study was funded by Lund University and Skane University Hospital. U Olsson-Strömberg, P Koskenvesa, and D Žáčková reported consulting for, being on speaker’s and advisory boards, or receiving honoraria from various pharmaceutical companies. The remaining authors had no disclosures.

Source: Richter J et al. Leukemia. 2021 Feb 15. doi: 10.1038/s41375-021-01173-w.

Key clinical point: Late relapses do occur after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic-phase chronic myeloid leukemia (CML-CP) in treatment-free remission (TFR) at 36 months, with molecular response (MR) status at 36 months being highly predictive of subsequent molecular relapse.

Major finding: During a follow-up of 72 months, 10.8% of patients in TFR at 36 months lost major MR. Not being in MR4 at 36 months of TKI discontinuation was associated with an 85% higher risk of molecular relapse during the subsequent 3 years.

Study details: Findings are from the 6-year follow-up (AFTER-SKI) of 111 patients with CML-CP who were in TFR at 36 months after TKI discontinuation from the EURO-SKI trial.

Disclosures: This study was funded by Lund University and Skane University Hospital. U Olsson-Strömberg, P Koskenvesa, and D Žáčková reported consulting for, being on speaker’s and advisory boards, or receiving honoraria from various pharmaceutical companies. The remaining authors had no disclosures.

Source: Richter J et al. Leukemia. 2021 Feb 15. doi: 10.1038/s41375-021-01173-w.

Key clinical point: Late relapses do occur after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic-phase chronic myeloid leukemia (CML-CP) in treatment-free remission (TFR) at 36 months, with molecular response (MR) status at 36 months being highly predictive of subsequent molecular relapse.

Major finding: During a follow-up of 72 months, 10.8% of patients in TFR at 36 months lost major MR. Not being in MR4 at 36 months of TKI discontinuation was associated with an 85% higher risk of molecular relapse during the subsequent 3 years.

Study details: Findings are from the 6-year follow-up (AFTER-SKI) of 111 patients with CML-CP who were in TFR at 36 months after TKI discontinuation from the EURO-SKI trial.

Disclosures: This study was funded by Lund University and Skane University Hospital. U Olsson-Strömberg, P Koskenvesa, and D Žáčková reported consulting for, being on speaker’s and advisory boards, or receiving honoraria from various pharmaceutical companies. The remaining authors had no disclosures.

Source: Richter J et al. Leukemia. 2021 Feb 15. doi: 10.1038/s41375-021-01173-w.

Key clinical point: Combination of imatinib (IM) with cytarabine (AraC) or pegylated interferon alpha2a (PegIFN-α2a) or a higher IM dose (600 mg; IM-600) did not improve long-term survival vs. IM 400 mg (IM-400) in patients with chronic myeloid leukemia in the chronic phase (CML-CP).

Major finding: At 15 years, overall survival was similar across IM-400 (85%; 95% confidence interval [CI], 78%-90%), IM-600 (83%; 95% CI, 75%-88%), IM-400+AraC (80%; 95% CI, 73%-85%), and IM-400+PegIFN-α2a (82%; 95% CI, 75%-87%) arms. Progression-free survival was also similar between arms.

Study details: Findings are from French SPIRIT phase 3 trial including 787 patients with CML-CP randomly allocated to frontline treatment with IM-400 (n=223), IM-600 (n=171), IM-400+AraC (n=172), and IM-400+PegIFN-α2a (n=221).

Disclosures: The trial was supported by grants from the French Minister of Health, Novartis, and Roche Pharma. The lead author reported ties with Novartis, Roche, BMS, and Celgene. Some of the other authors also declared receiving honoraria and/or research support from various pharmaceutical companies.

Source: Guilhot F et al. Leukemia. 2021 Jan 22. doi: 10.1038/s41375-020-01117-w.

Key clinical point: Combination of imatinib (IM) with cytarabine (AraC) or pegylated interferon alpha2a (PegIFN-α2a) or a higher IM dose (600 mg; IM-600) did not improve long-term survival vs. IM 400 mg (IM-400) in patients with chronic myeloid leukemia in the chronic phase (CML-CP).

Major finding: At 15 years, overall survival was similar across IM-400 (85%; 95% confidence interval [CI], 78%-90%), IM-600 (83%; 95% CI, 75%-88%), IM-400+AraC (80%; 95% CI, 73%-85%), and IM-400+PegIFN-α2a (82%; 95% CI, 75%-87%) arms. Progression-free survival was also similar between arms.

Study details: Findings are from French SPIRIT phase 3 trial including 787 patients with CML-CP randomly allocated to frontline treatment with IM-400 (n=223), IM-600 (n=171), IM-400+AraC (n=172), and IM-400+PegIFN-α2a (n=221).

Disclosures: The trial was supported by grants from the French Minister of Health, Novartis, and Roche Pharma. The lead author reported ties with Novartis, Roche, BMS, and Celgene. Some of the other authors also declared receiving honoraria and/or research support from various pharmaceutical companies.

Source: Guilhot F et al. Leukemia. 2021 Jan 22. doi: 10.1038/s41375-020-01117-w.

Key clinical point: Combination of imatinib (IM) with cytarabine (AraC) or pegylated interferon alpha2a (PegIFN-α2a) or a higher IM dose (600 mg; IM-600) did not improve long-term survival vs. IM 400 mg (IM-400) in patients with chronic myeloid leukemia in the chronic phase (CML-CP).

Major finding: At 15 years, overall survival was similar across IM-400 (85%; 95% confidence interval [CI], 78%-90%), IM-600 (83%; 95% CI, 75%-88%), IM-400+AraC (80%; 95% CI, 73%-85%), and IM-400+PegIFN-α2a (82%; 95% CI, 75%-87%) arms. Progression-free survival was also similar between arms.

Study details: Findings are from French SPIRIT phase 3 trial including 787 patients with CML-CP randomly allocated to frontline treatment with IM-400 (n=223), IM-600 (n=171), IM-400+AraC (n=172), and IM-400+PegIFN-α2a (n=221).

Disclosures: The trial was supported by grants from the French Minister of Health, Novartis, and Roche Pharma. The lead author reported ties with Novartis, Roche, BMS, and Celgene. Some of the other authors also declared receiving honoraria and/or research support from various pharmaceutical companies.

Source: Guilhot F et al. Leukemia. 2021 Jan 22. doi: 10.1038/s41375-020-01117-w.

Long term CML follow up clinical trials are quite important tool to monitor the late or new adverse side effects as well as to conform the efficacy in the long run of the drug tested. However, there are not so many examples on CML outside the IRIS trial. Recently, Kantarjian and collaborators had published the 10 years follow up on the ENESTnd trial that compared the use of two doses of nilotinib (300md bid and 400 mg bid) against imatinib (400mg qd). Once again, the study showed a higher cumulative molecular response rates (MMR: 77% vs 79% vs 62% and MR4.5:61% vs61% vs 39%) that translated in a higher proportion of patient candidates for TFR (48% vs 47% vs 29%). Furthermore, nilotinib was associated to lower rates of disease progression compare with imatinib. As previously described there were no differences in terms of PFS or OS between the three arms. In terms of toxicity, although the overall adverse effects were similar, a higher incidence of cardiovascular events were reported (16% vs 23% vs 3%). The incidence of these CVE on the nilotinib arm continue to occur at the same rate each year and were more associated with high and intermediate Framingham risk. Overall, the trial supports the use of nilotinib 300mg twice daily as front line therapy for CML for optimal long terms outcomes with a positive benefit-risk in the context of TFR as treatment goal.

One of the important aspects of the CVE secondary to second generation TKIs is the identification of high-risk populations as well as biomarkers that may help to prevent these episodes. In this regard, Italian investigators recently published a study of 369 patients treated with nilotinib where, besides stratification by the new coronary risk evaluation (SCORE), they measure the lipids levels at various times point since the initiation of therapy and identify cholesterol greater than 200mg/dL and LDL greater than 70 mg/dL as predictors factor for increased risk of CVE as well as a high SCORE risk. The authors suggest an aggressive follow up on lipids levels in patients taking nilotinib and the incorporation of cholesterol lowering medications.

Although the incidence of CVE has been more classically associated with nilotinib and ponatinib, more recent evidence suggests that the use of second generation TKIs in general can increase the risk of CVE in CML patients in comparison with the general population; however, it is hard to study the contribution of the disease itself. Leong and collaborators recently published a very large retrospective analysis of more than 4,000 CML patients that were age and sex matched with 42,000 controls without CML, showing that the incidence of these events is higher before and after the introduction of TKIs in 2001.

Javier Pinilla-Ibarz, MD, PhD
Senior Member
Lymphoma Section Head and
Director of Immunotherapy
Malignant Hematology Department
H. Lee Moffitt Cancer Center & Research Institute
 

Long term CML follow up clinical trials are quite important tool to monitor the late or new adverse side effects as well as to conform the efficacy in the long run of the drug tested. However, there are not so many examples on CML outside the IRIS trial. Recently, Kantarjian and collaborators had published the 10 years follow up on the ENESTnd trial that compared the use of two doses of nilotinib (300md bid and 400 mg bid) against imatinib (400mg qd). Once again, the study showed a higher cumulative molecular response rates (MMR: 77% vs 79% vs 62% and MR4.5:61% vs61% vs 39%) that translated in a higher proportion of patient candidates for TFR (48% vs 47% vs 29%). Furthermore, nilotinib was associated to lower rates of disease progression compare with imatinib. As previously described there were no differences in terms of PFS or OS between the three arms. In terms of toxicity, although the overall adverse effects were similar, a higher incidence of cardiovascular events were reported (16% vs 23% vs 3%). The incidence of these CVE on the nilotinib arm continue to occur at the same rate each year and were more associated with high and intermediate Framingham risk. Overall, the trial supports the use of nilotinib 300mg twice daily as front line therapy for CML for optimal long terms outcomes with a positive benefit-risk in the context of TFR as treatment goal.

One of the important aspects of the CVE secondary to second generation TKIs is the identification of high-risk populations as well as biomarkers that may help to prevent these episodes. In this regard, Italian investigators recently published a study of 369 patients treated with nilotinib where, besides stratification by the new coronary risk evaluation (SCORE), they measure the lipids levels at various times point since the initiation of therapy and identify cholesterol greater than 200mg/dL and LDL greater than 70 mg/dL as predictors factor for increased risk of CVE as well as a high SCORE risk. The authors suggest an aggressive follow up on lipids levels in patients taking nilotinib and the incorporation of cholesterol lowering medications.

Although the incidence of CVE has been more classically associated with nilotinib and ponatinib, more recent evidence suggests that the use of second generation TKIs in general can increase the risk of CVE in CML patients in comparison with the general population; however, it is hard to study the contribution of the disease itself. Leong and collaborators recently published a very large retrospective analysis of more than 4,000 CML patients that were age and sex matched with 42,000 controls without CML, showing that the incidence of these events is higher before and after the introduction of TKIs in 2001.

Javier Pinilla-Ibarz, MD, PhD
Senior Member
Lymphoma Section Head and
Director of Immunotherapy
Malignant Hematology Department
H. Lee Moffitt Cancer Center & Research Institute
 

Long term CML follow up clinical trials are quite important tool to monitor the late or new adverse side effects as well as to conform the efficacy in the long run of the drug tested. However, there are not so many examples on CML outside the IRIS trial. Recently, Kantarjian and collaborators had published the 10 years follow up on the ENESTnd trial that compared the use of two doses of nilotinib (300md bid and 400 mg bid) against imatinib (400mg qd). Once again, the study showed a higher cumulative molecular response rates (MMR: 77% vs 79% vs 62% and MR4.5:61% vs61% vs 39%) that translated in a higher proportion of patient candidates for TFR (48% vs 47% vs 29%). Furthermore, nilotinib was associated to lower rates of disease progression compare with imatinib. As previously described there were no differences in terms of PFS or OS between the three arms. In terms of toxicity, although the overall adverse effects were similar, a higher incidence of cardiovascular events were reported (16% vs 23% vs 3%). The incidence of these CVE on the nilotinib arm continue to occur at the same rate each year and were more associated with high and intermediate Framingham risk. Overall, the trial supports the use of nilotinib 300mg twice daily as front line therapy for CML for optimal long terms outcomes with a positive benefit-risk in the context of TFR as treatment goal.

One of the important aspects of the CVE secondary to second generation TKIs is the identification of high-risk populations as well as biomarkers that may help to prevent these episodes. In this regard, Italian investigators recently published a study of 369 patients treated with nilotinib where, besides stratification by the new coronary risk evaluation (SCORE), they measure the lipids levels at various times point since the initiation of therapy and identify cholesterol greater than 200mg/dL and LDL greater than 70 mg/dL as predictors factor for increased risk of CVE as well as a high SCORE risk. The authors suggest an aggressive follow up on lipids levels in patients taking nilotinib and the incorporation of cholesterol lowering medications.

Although the incidence of CVE has been more classically associated with nilotinib and ponatinib, more recent evidence suggests that the use of second generation TKIs in general can increase the risk of CVE in CML patients in comparison with the general population; however, it is hard to study the contribution of the disease itself. Leong and collaborators recently published a very large retrospective analysis of more than 4,000 CML patients that were age and sex matched with 42,000 controls without CML, showing that the incidence of these events is higher before and after the introduction of TKIs in 2001.

Javier Pinilla-Ibarz, MD, PhD
Senior Member
Lymphoma Section Head and
Director of Immunotherapy
Malignant Hematology Department
H. Lee Moffitt Cancer Center & Research Institute
 

Key clinical point: In 10-year follow-up of ENESTnd trial, nilotinib demonstrated benefits over imatinib for various clinical outcomes in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP).

Major finding: Cumulative 10-year rates of treatment-free remission eligibility and molecular response rate with nilotinib 300 mg and 400 mg vs. imatinib was 48.6% and 47.3% vs. 29.7% and 77.7% and 79.7% vs. 62.5%, respectively. Progression to accelerated (6 and 4 vs. 11) or blast (6 and 6 vs. 14) phase was lower with nilotinib 300 mg and 400 mg vs. imatinib, respectively. Overall, the frequency of adverse events was similar, but rates of cardiovascular events were higher with nilotinib.

Study details: ENESTnd, a phase 3 study, randomly allocated patients with newly diagnosed CML-CP to receive nilotinib 300 mg twice daily (n=282), nilotinib 400 mg twice daily (n=281), or imatinib 400 mg once daily (n=283).

Disclosures: The study was funded by Novartis Pharmaceuticals Corporation. The presenting author reported ties with Pharmaceuticals companies including Novartis. Some of the study investigators reported being an employee of, receiving grants, honoraria, support, and/or consulting for Novartis and other pharmaceutical companies.

Source: Kantarjian HM et al. Leukemia. 2021 Jan 7. doi: 10.1038/s41375-020-01111-2.

Key clinical point: In 10-year follow-up of ENESTnd trial, nilotinib demonstrated benefits over imatinib for various clinical outcomes in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP).

Major finding: Cumulative 10-year rates of treatment-free remission eligibility and molecular response rate with nilotinib 300 mg and 400 mg vs. imatinib was 48.6% and 47.3% vs. 29.7% and 77.7% and 79.7% vs. 62.5%, respectively. Progression to accelerated (6 and 4 vs. 11) or blast (6 and 6 vs. 14) phase was lower with nilotinib 300 mg and 400 mg vs. imatinib, respectively. Overall, the frequency of adverse events was similar, but rates of cardiovascular events were higher with nilotinib.

Study details: ENESTnd, a phase 3 study, randomly allocated patients with newly diagnosed CML-CP to receive nilotinib 300 mg twice daily (n=282), nilotinib 400 mg twice daily (n=281), or imatinib 400 mg once daily (n=283).

Disclosures: The study was funded by Novartis Pharmaceuticals Corporation. The presenting author reported ties with Pharmaceuticals companies including Novartis. Some of the study investigators reported being an employee of, receiving grants, honoraria, support, and/or consulting for Novartis and other pharmaceutical companies.

Source: Kantarjian HM et al. Leukemia. 2021 Jan 7. doi: 10.1038/s41375-020-01111-2.

Key clinical point: In 10-year follow-up of ENESTnd trial, nilotinib demonstrated benefits over imatinib for various clinical outcomes in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP).

Major finding: Cumulative 10-year rates of treatment-free remission eligibility and molecular response rate with nilotinib 300 mg and 400 mg vs. imatinib was 48.6% and 47.3% vs. 29.7% and 77.7% and 79.7% vs. 62.5%, respectively. Progression to accelerated (6 and 4 vs. 11) or blast (6 and 6 vs. 14) phase was lower with nilotinib 300 mg and 400 mg vs. imatinib, respectively. Overall, the frequency of adverse events was similar, but rates of cardiovascular events were higher with nilotinib.

Study details: ENESTnd, a phase 3 study, randomly allocated patients with newly diagnosed CML-CP to receive nilotinib 300 mg twice daily (n=282), nilotinib 400 mg twice daily (n=281), or imatinib 400 mg once daily (n=283).

Disclosures: The study was funded by Novartis Pharmaceuticals Corporation. The presenting author reported ties with Pharmaceuticals companies including Novartis. Some of the study investigators reported being an employee of, receiving grants, honoraria, support, and/or consulting for Novartis and other pharmaceutical companies.

Source: Kantarjian HM et al. Leukemia. 2021 Jan 7. doi: 10.1038/s41375-020-01111-2.

Key clinical point: Patients with chronic myeloid leukemia (CML) in the era of tyrosine kinase inhibitors (TKIs) are at a greater risk for adverse cardiovascular events (ACEs) compared with the general population.

Major finding: From 2001 onwards, the risk for major ACEs (subdistribution hazard ratio [SHR], 1.27; 95% confidence interval [CI], 0.96-1.43) and cardiovascular death (SHR, 0.99; 95% CI, 0.84-1.18) was similar between patients with vs. without CML. However, before 2001, the risk for major ACE (SHR, 0.59; 95% CI, 0.46-0.76) and cardiovascular death (SHR, 0.43; 95% CI, 0.36-0.52) was lower in patients with vs. without CML.

Study details: A population-based retrospective study of 4,238 patients with CML who were age- and sex-matched with 42,380 controls without CML.

Disclosures: The study was funded by the Population Health Research Institute, McMaster University, and Institute of Clinical and Evaluative Sciences. The authors reported no conflicts of interest.

Source: Leong D et al. Heart. 2021 Jan 8. doi: 10.1136/heartjnl-2020-318251.

Key clinical point: Patients with chronic myeloid leukemia (CML) in the era of tyrosine kinase inhibitors (TKIs) are at a greater risk for adverse cardiovascular events (ACEs) compared with the general population.

Major finding: From 2001 onwards, the risk for major ACEs (subdistribution hazard ratio [SHR], 1.27; 95% confidence interval [CI], 0.96-1.43) and cardiovascular death (SHR, 0.99; 95% CI, 0.84-1.18) was similar between patients with vs. without CML. However, before 2001, the risk for major ACE (SHR, 0.59; 95% CI, 0.46-0.76) and cardiovascular death (SHR, 0.43; 95% CI, 0.36-0.52) was lower in patients with vs. without CML.

Study details: A population-based retrospective study of 4,238 patients with CML who were age- and sex-matched with 42,380 controls without CML.

Disclosures: The study was funded by the Population Health Research Institute, McMaster University, and Institute of Clinical and Evaluative Sciences. The authors reported no conflicts of interest.

Source: Leong D et al. Heart. 2021 Jan 8. doi: 10.1136/heartjnl-2020-318251.

Key clinical point: Patients with chronic myeloid leukemia (CML) in the era of tyrosine kinase inhibitors (TKIs) are at a greater risk for adverse cardiovascular events (ACEs) compared with the general population.

Major finding: From 2001 onwards, the risk for major ACEs (subdistribution hazard ratio [SHR], 1.27; 95% confidence interval [CI], 0.96-1.43) and cardiovascular death (SHR, 0.99; 95% CI, 0.84-1.18) was similar between patients with vs. without CML. However, before 2001, the risk for major ACE (SHR, 0.59; 95% CI, 0.46-0.76) and cardiovascular death (SHR, 0.43; 95% CI, 0.36-0.52) was lower in patients with vs. without CML.

Study details: A population-based retrospective study of 4,238 patients with CML who were age- and sex-matched with 42,380 controls without CML.

Disclosures: The study was funded by the Population Health Research Institute, McMaster University, and Institute of Clinical and Evaluative Sciences. The authors reported no conflicts of interest.

Source: Leong D et al. Heart. 2021 Jan 8. doi: 10.1136/heartjnl-2020-318251.