Clinical Edge Journal Scan

CPX-351 is a liposomal cytarabine and daunorubicin. It was FDA approved in 2017 for the treatment of patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The approval was based on the results from a randomized trial comparing CPX-351 vs standard 7 +3 chemotherapy in patients older that 65 with t-AML or AML-MRC. The 5-year results from that study were recently published by Lancet et al. At 5 years of follow-up, CPX-351 continued to show benefit in older patients with t-AML or AML-MRC vs standard chemotherapy with cytarabine for 7 days and daunorubicin for 3 days (7+3) . The median OS in favor of CPX-351 vs 7+3 group was maintained (hazard ratio, 0.70; 95% confidence interval [CI], 0.55-0.91). At 5 years, survival estimates were higher for CPX-351 vs 7+3 (18% [95% CI, 12%-25%] vs 8% [95% CI, 4%-13%]). Overall, 5% of deaths in both groups were considered related to the study treatment. Overall, more patients treated with CPX-351 were able to proceed to stem cell transplantation (SCT) compared to those treated with 7 + 3 (35% vs 25%).

The 3-year overall survival from SCT was 56% vs 23% for patients treated with CPX-351 vs 7 +3. Of the responding patients who did not proceed to SCT, only 3 patients were alive at 5 years. Although this data is encouraging, it demonstrates that we have a long way to go to improve the outcome of these patients. In addition, more patients who achieve remission should proceed to SCT in order to improve the survival of this patient population (Lancet JE et al). In terms of supportive care during induction chemotherapy, two published studies this month evaluated two approaches to aiming to decrease the morbidity from infections: prospective monitoring for fungal infections and the use of romyelocel with G-CSF. Prospectively monitoring for fungal infections was performed as an observation study imbedded within a phase 3 Children’s Oncology Group trial (ACCL0933). The study included 471 patients with AML (age, 3 months-30 years) receiving fluconazole (n=235) or caspofungin (n=236).

Twice-weekly surveillance with galactomannan enzyme immunoassay (GM-EIA) and b-D-glucan (BDG) assay were performed in all patients. The negative predictive value was greater than 99% for an individual or combination of GM-EIA and BDG assays. However, true positive results were not observed in any sample collected within 7 days of an invasive aspergillosis/candidiasis diagnosis, resulting in sensitivity and positive predictive value for each test of 0%. This approach was ineffective at detecting invasive fungal diseases (IFDs) in children, adolescents, and young adults with acute myeloid leukemia (AML) receiving antifungal prophylaxis (Fisher BT et al).

A different approach to reduce infection morbidity and mortality during induction chemotherapy is the administration of romyelocel. Myeloid progenitor cells are cells that can produce granulocytes but have no long-term reconstitution capability.  Romyelocel is a cryopreserved product, of MPC manufactured by ex vivo expansion of CD34⁺ hematopoietic stem cells. Romyelocel is capable of producing granulocytes, and thereby may reduce the severity or duration of neutropenic fevers. This phase 2 study included 163 patients with de novo AML receiving induction chemotherapy. Evaluable patients (n=120) were randomly assigned to receive either romyelocel-L plus G-CSF (n=59) or G-CSF monotherapy (n=61). From days 15 to 28, romyelocel-L plus G-CSF vs G-CSF monotherapy significantly reduced the mean duration of febrile episodes (2.36 days vs 3.90 days; P = .02) and incidence of infections (6.8% vs 27.9%; P = .0013). Length of hospitalization was significantly shorter in the romyelocel-L plus G-CSF vs G-CSF monotherapy group (25.5 days vs 28.7 days; P = .002). These results are encouraging, and a phase III trial is suggested by the authors. (Desai PM et al).

Finally, a study by MDACC reported disappointing results with the use of venetoclax in patients with tp53 mutation. Findings are from a retrospective analysis of 238 patients with newly diagnosed TP53-mutated AML treated with either VEN-based (n=58) or non-VEN-based (n=180) therapies. The addition of venetoclax to standard treatment regimens (VEN-based) did not improve clinical outcomes in patients with TP53-mutated acute myeloid leukemia (AML), highlighting the need for novel therapies in this patient population. Overall, there was no significant differences in overall survival (median, 5.7 months vs 6.6 months; P = .4), relapse-free survival (median, 3.5 months vs 4.7 months; P = .43), 4-week mortality (7% vs 10%; P = .5), and 8-week mortality (22% vs 17%; P = .4) in patients receiving VEN-based vs non-VEN-based therapies (Venugopal S et al). Clearly, better therapies are needed for this patient population.

CPX-351 is a liposomal cytarabine and daunorubicin. It was FDA approved in 2017 for the treatment of patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The approval was based on the results from a randomized trial comparing CPX-351 vs standard 7 +3 chemotherapy in patients older that 65 with t-AML or AML-MRC. The 5-year results from that study were recently published by Lancet et al. At 5 years of follow-up, CPX-351 continued to show benefit in older patients with t-AML or AML-MRC vs standard chemotherapy with cytarabine for 7 days and daunorubicin for 3 days (7+3) . The median OS in favor of CPX-351 vs 7+3 group was maintained (hazard ratio, 0.70; 95% confidence interval [CI], 0.55-0.91). At 5 years, survival estimates were higher for CPX-351 vs 7+3 (18% [95% CI, 12%-25%] vs 8% [95% CI, 4%-13%]). Overall, 5% of deaths in both groups were considered related to the study treatment. Overall, more patients treated with CPX-351 were able to proceed to stem cell transplantation (SCT) compared to those treated with 7 + 3 (35% vs 25%).

The 3-year overall survival from SCT was 56% vs 23% for patients treated with CPX-351 vs 7 +3. Of the responding patients who did not proceed to SCT, only 3 patients were alive at 5 years. Although this data is encouraging, it demonstrates that we have a long way to go to improve the outcome of these patients. In addition, more patients who achieve remission should proceed to SCT in order to improve the survival of this patient population (Lancet JE et al). In terms of supportive care during induction chemotherapy, two published studies this month evaluated two approaches to aiming to decrease the morbidity from infections: prospective monitoring for fungal infections and the use of romyelocel with G-CSF. Prospectively monitoring for fungal infections was performed as an observation study imbedded within a phase 3 Children’s Oncology Group trial (ACCL0933). The study included 471 patients with AML (age, 3 months-30 years) receiving fluconazole (n=235) or caspofungin (n=236).

Twice-weekly surveillance with galactomannan enzyme immunoassay (GM-EIA) and b-D-glucan (BDG) assay were performed in all patients. The negative predictive value was greater than 99% for an individual or combination of GM-EIA and BDG assays. However, true positive results were not observed in any sample collected within 7 days of an invasive aspergillosis/candidiasis diagnosis, resulting in sensitivity and positive predictive value for each test of 0%. This approach was ineffective at detecting invasive fungal diseases (IFDs) in children, adolescents, and young adults with acute myeloid leukemia (AML) receiving antifungal prophylaxis (Fisher BT et al).

A different approach to reduce infection morbidity and mortality during induction chemotherapy is the administration of romyelocel. Myeloid progenitor cells are cells that can produce granulocytes but have no long-term reconstitution capability.  Romyelocel is a cryopreserved product, of MPC manufactured by ex vivo expansion of CD34⁺ hematopoietic stem cells. Romyelocel is capable of producing granulocytes, and thereby may reduce the severity or duration of neutropenic fevers. This phase 2 study included 163 patients with de novo AML receiving induction chemotherapy. Evaluable patients (n=120) were randomly assigned to receive either romyelocel-L plus G-CSF (n=59) or G-CSF monotherapy (n=61). From days 15 to 28, romyelocel-L plus G-CSF vs G-CSF monotherapy significantly reduced the mean duration of febrile episodes (2.36 days vs 3.90 days; P = .02) and incidence of infections (6.8% vs 27.9%; P = .0013). Length of hospitalization was significantly shorter in the romyelocel-L plus G-CSF vs G-CSF monotherapy group (25.5 days vs 28.7 days; P = .002). These results are encouraging, and a phase III trial is suggested by the authors. (Desai PM et al).

Finally, a study by MDACC reported disappointing results with the use of venetoclax in patients with tp53 mutation. Findings are from a retrospective analysis of 238 patients with newly diagnosed TP53-mutated AML treated with either VEN-based (n=58) or non-VEN-based (n=180) therapies. The addition of venetoclax to standard treatment regimens (VEN-based) did not improve clinical outcomes in patients with TP53-mutated acute myeloid leukemia (AML), highlighting the need for novel therapies in this patient population. Overall, there was no significant differences in overall survival (median, 5.7 months vs 6.6 months; P = .4), relapse-free survival (median, 3.5 months vs 4.7 months; P = .43), 4-week mortality (7% vs 10%; P = .5), and 8-week mortality (22% vs 17%; P = .4) in patients receiving VEN-based vs non-VEN-based therapies (Venugopal S et al). Clearly, better therapies are needed for this patient population.

CPX-351 is a liposomal cytarabine and daunorubicin. It was FDA approved in 2017 for the treatment of patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The approval was based on the results from a randomized trial comparing CPX-351 vs standard 7 +3 chemotherapy in patients older that 65 with t-AML or AML-MRC. The 5-year results from that study were recently published by Lancet et al. At 5 years of follow-up, CPX-351 continued to show benefit in older patients with t-AML or AML-MRC vs standard chemotherapy with cytarabine for 7 days and daunorubicin for 3 days (7+3) . The median OS in favor of CPX-351 vs 7+3 group was maintained (hazard ratio, 0.70; 95% confidence interval [CI], 0.55-0.91). At 5 years, survival estimates were higher for CPX-351 vs 7+3 (18% [95% CI, 12%-25%] vs 8% [95% CI, 4%-13%]). Overall, 5% of deaths in both groups were considered related to the study treatment. Overall, more patients treated with CPX-351 were able to proceed to stem cell transplantation (SCT) compared to those treated with 7 + 3 (35% vs 25%).

The 3-year overall survival from SCT was 56% vs 23% for patients treated with CPX-351 vs 7 +3. Of the responding patients who did not proceed to SCT, only 3 patients were alive at 5 years. Although this data is encouraging, it demonstrates that we have a long way to go to improve the outcome of these patients. In addition, more patients who achieve remission should proceed to SCT in order to improve the survival of this patient population (Lancet JE et al). In terms of supportive care during induction chemotherapy, two published studies this month evaluated two approaches to aiming to decrease the morbidity from infections: prospective monitoring for fungal infections and the use of romyelocel with G-CSF. Prospectively monitoring for fungal infections was performed as an observation study imbedded within a phase 3 Children’s Oncology Group trial (ACCL0933). The study included 471 patients with AML (age, 3 months-30 years) receiving fluconazole (n=235) or caspofungin (n=236).

Twice-weekly surveillance with galactomannan enzyme immunoassay (GM-EIA) and b-D-glucan (BDG) assay were performed in all patients. The negative predictive value was greater than 99% for an individual or combination of GM-EIA and BDG assays. However, true positive results were not observed in any sample collected within 7 days of an invasive aspergillosis/candidiasis diagnosis, resulting in sensitivity and positive predictive value for each test of 0%. This approach was ineffective at detecting invasive fungal diseases (IFDs) in children, adolescents, and young adults with acute myeloid leukemia (AML) receiving antifungal prophylaxis (Fisher BT et al).

A different approach to reduce infection morbidity and mortality during induction chemotherapy is the administration of romyelocel. Myeloid progenitor cells are cells that can produce granulocytes but have no long-term reconstitution capability.  Romyelocel is a cryopreserved product, of MPC manufactured by ex vivo expansion of CD34⁺ hematopoietic stem cells. Romyelocel is capable of producing granulocytes, and thereby may reduce the severity or duration of neutropenic fevers. This phase 2 study included 163 patients with de novo AML receiving induction chemotherapy. Evaluable patients (n=120) were randomly assigned to receive either romyelocel-L plus G-CSF (n=59) or G-CSF monotherapy (n=61). From days 15 to 28, romyelocel-L plus G-CSF vs G-CSF monotherapy significantly reduced the mean duration of febrile episodes (2.36 days vs 3.90 days; P = .02) and incidence of infections (6.8% vs 27.9%; P = .0013). Length of hospitalization was significantly shorter in the romyelocel-L plus G-CSF vs G-CSF monotherapy group (25.5 days vs 28.7 days; P = .002). These results are encouraging, and a phase III trial is suggested by the authors. (Desai PM et al).

Finally, a study by MDACC reported disappointing results with the use of venetoclax in patients with tp53 mutation. Findings are from a retrospective analysis of 238 patients with newly diagnosed TP53-mutated AML treated with either VEN-based (n=58) or non-VEN-based (n=180) therapies. The addition of venetoclax to standard treatment regimens (VEN-based) did not improve clinical outcomes in patients with TP53-mutated acute myeloid leukemia (AML), highlighting the need for novel therapies in this patient population. Overall, there was no significant differences in overall survival (median, 5.7 months vs 6.6 months; P = .4), relapse-free survival (median, 3.5 months vs 4.7 months; P = .43), 4-week mortality (7% vs 10%; P = .5), and 8-week mortality (22% vs 17%; P = .4) in patients receiving VEN-based vs non-VEN-based therapies (Venugopal S et al). Clearly, better therapies are needed for this patient population.

Program death-ligand 1 (PD-L1) inhibition suppresses tumor activity via modulation of immune and tumor cell interaction. TNBC is characterized by higher PD-L1 expression and increased immune infiltration, compared to other subtypes. In the randomized, phase 3 IMpassion130 trial, among 902 patients who were treatment naïve in the metastatic TNBC setting, an exploratory analysis in the PD-L1-positive population demonstrated a clinically meaningful OS benefit with atezolizumab + nab-paclitaxel compared to placebo + nab-paclitaxel (25.4 vs 17.9 months; HR 0.67) (Emens et al). Additionally, the phase 3 KEYNOTE-355 trial demonstrated PFS benefit among patients with mTNBC with combined positive score (CPS) ≥10 with pembrolizumab + chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) versus placebo + chemotherapy (mPFS 9.7 vs 5.6 months; HR 0.65, 95% CI 0.49-0.86). These results are in contrast to the phase 3 IMpassion131 trial which found no statistically significant difference in PFS or OS among 651 patients with mTNBC randomized to atezolizumab + paclitaxel vs placebo + paclitaxel (PD-L1-positive population: PFS 6.0 vs 5.7 months, HR 0.82, 95% CI 0.60-1.12; OS 22.1 vs 28.3 months, HR 1.11, 95% CI 0.76-1.62) (Miles et al). The reasons underlying these differences remain unclear and warrant further investigation. Some thoughts raised include lack of information on BRCA status (which may serve as prognostic factor) in IMpassion131, concomitant use of steroids with paclitaxel, and allowance of sufficient long-term follow-up for generation of events. Regardless, these studies suggest chemotherapy backbone is relevant and the regimens utilized in IMpassion130 and KEYNOTE-355 have gained FDA approval in the first-line mTNBC setting.

The phase 3 CLEOPATRA trial has established the regimen of docetaxel + trastuzumab + pertuzumab as standard of care in the first-line setting for metastatic HER2-positive breast cancer with an OS benefit of 16 months compared to docetaxel + trastuzumab + placebo (57.1 vs 40.8 months; HR 0.69, 95% CI 0.58-0.82) with over 8 years of follow-up. PERUSE was a single-arm phase 3b study that investigated the safety and efficacy of trastuzumab + pertuzumab combined with various taxanes (docetaxel, paclitaxel or nab-paclitaxel) among 1426 patients with HER2+ mBC (Miles et al). In the overall population at follow-up of 5.7 years, median PFS and OS were 20.7 and 65.3 months, respectively, and were similar regardless of taxane backbone. Docetaxel was associated with higher incidences of neutropenia and febrile neutropenia. These results support consideration of an alternative taxane combined with trastuzumab + pertuzumab in this setting (for example paclitaxel) in patients who may not be ideal candidates for docetaxel.

In the second-line treatment setting for HER2+ mBC with prior exposure to trastuzumab and taxane, the phase 3 EMILIA study showed improvement in OS with T-DM1 vs capecitabine + lapatinib (mOS 29.9 vs 25.9 months, HR 0.75, 95% CI 0.64-0.88). Ethier et al explored real-world application and outcomes associated with pertuzumab and T-DM1 in the first- and second-line settings respectively, in a population-based, retrospective cohort study in Ontario, Canada. In the pertuzumab cohort, median OS and time on treatment were 43 and 4 months, respectively. In the T-DM1 cohort, median OS and time on treatment were 15 months and 4 months, respectively. Additionally, patients in the T-DM1 cohort who were pertuzumab-naïve appeared to do better, potentially suggesting less responsiveness to subsequent HER2-targeted treatment in the real world setting among those who received prior pertuzumab. Findings from this population study demonstrate inferior outcomes when compared to the pivotal CLEOPATRA and EMILIA trials, and highlight a gap between clinical trial and real-world observations (described by authors as efficacy-effectiveness gap). Potential etiologies for these differences include patient factors, prior therapies and delivery of care models, and convey the importance of recognizing this gap exists and optimizing any modifiable factors as trial data and novel therapies are applied to routine clinical practice.

References:

Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361-70.

Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828.

Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530.

Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742.

Program death-ligand 1 (PD-L1) inhibition suppresses tumor activity via modulation of immune and tumor cell interaction. TNBC is characterized by higher PD-L1 expression and increased immune infiltration, compared to other subtypes. In the randomized, phase 3 IMpassion130 trial, among 902 patients who were treatment naïve in the metastatic TNBC setting, an exploratory analysis in the PD-L1-positive population demonstrated a clinically meaningful OS benefit with atezolizumab + nab-paclitaxel compared to placebo + nab-paclitaxel (25.4 vs 17.9 months; HR 0.67) (Emens et al). Additionally, the phase 3 KEYNOTE-355 trial demonstrated PFS benefit among patients with mTNBC with combined positive score (CPS) ≥10 with pembrolizumab + chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) versus placebo + chemotherapy (mPFS 9.7 vs 5.6 months; HR 0.65, 95% CI 0.49-0.86). These results are in contrast to the phase 3 IMpassion131 trial which found no statistically significant difference in PFS or OS among 651 patients with mTNBC randomized to atezolizumab + paclitaxel vs placebo + paclitaxel (PD-L1-positive population: PFS 6.0 vs 5.7 months, HR 0.82, 95% CI 0.60-1.12; OS 22.1 vs 28.3 months, HR 1.11, 95% CI 0.76-1.62) (Miles et al). The reasons underlying these differences remain unclear and warrant further investigation. Some thoughts raised include lack of information on BRCA status (which may serve as prognostic factor) in IMpassion131, concomitant use of steroids with paclitaxel, and allowance of sufficient long-term follow-up for generation of events. Regardless, these studies suggest chemotherapy backbone is relevant and the regimens utilized in IMpassion130 and KEYNOTE-355 have gained FDA approval in the first-line mTNBC setting.

The phase 3 CLEOPATRA trial has established the regimen of docetaxel + trastuzumab + pertuzumab as standard of care in the first-line setting for metastatic HER2-positive breast cancer with an OS benefit of 16 months compared to docetaxel + trastuzumab + placebo (57.1 vs 40.8 months; HR 0.69, 95% CI 0.58-0.82) with over 8 years of follow-up. PERUSE was a single-arm phase 3b study that investigated the safety and efficacy of trastuzumab + pertuzumab combined with various taxanes (docetaxel, paclitaxel or nab-paclitaxel) among 1426 patients with HER2+ mBC (Miles et al). In the overall population at follow-up of 5.7 years, median PFS and OS were 20.7 and 65.3 months, respectively, and were similar regardless of taxane backbone. Docetaxel was associated with higher incidences of neutropenia and febrile neutropenia. These results support consideration of an alternative taxane combined with trastuzumab + pertuzumab in this setting (for example paclitaxel) in patients who may not be ideal candidates for docetaxel.

In the second-line treatment setting for HER2+ mBC with prior exposure to trastuzumab and taxane, the phase 3 EMILIA study showed improvement in OS with T-DM1 vs capecitabine + lapatinib (mOS 29.9 vs 25.9 months, HR 0.75, 95% CI 0.64-0.88). Ethier et al explored real-world application and outcomes associated with pertuzumab and T-DM1 in the first- and second-line settings respectively, in a population-based, retrospective cohort study in Ontario, Canada. In the pertuzumab cohort, median OS and time on treatment were 43 and 4 months, respectively. In the T-DM1 cohort, median OS and time on treatment were 15 months and 4 months, respectively. Additionally, patients in the T-DM1 cohort who were pertuzumab-naïve appeared to do better, potentially suggesting less responsiveness to subsequent HER2-targeted treatment in the real world setting among those who received prior pertuzumab. Findings from this population study demonstrate inferior outcomes when compared to the pivotal CLEOPATRA and EMILIA trials, and highlight a gap between clinical trial and real-world observations (described by authors as efficacy-effectiveness gap). Potential etiologies for these differences include patient factors, prior therapies and delivery of care models, and convey the importance of recognizing this gap exists and optimizing any modifiable factors as trial data and novel therapies are applied to routine clinical practice.

References:

Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361-70.

Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828.

Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530.

Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742.

Program death-ligand 1 (PD-L1) inhibition suppresses tumor activity via modulation of immune and tumor cell interaction. TNBC is characterized by higher PD-L1 expression and increased immune infiltration, compared to other subtypes. In the randomized, phase 3 IMpassion130 trial, among 902 patients who were treatment naïve in the metastatic TNBC setting, an exploratory analysis in the PD-L1-positive population demonstrated a clinically meaningful OS benefit with atezolizumab + nab-paclitaxel compared to placebo + nab-paclitaxel (25.4 vs 17.9 months; HR 0.67) (Emens et al). Additionally, the phase 3 KEYNOTE-355 trial demonstrated PFS benefit among patients with mTNBC with combined positive score (CPS) ≥10 with pembrolizumab + chemotherapy (nab-paclitaxel, paclitaxel or gemcitabine/carboplatin) versus placebo + chemotherapy (mPFS 9.7 vs 5.6 months; HR 0.65, 95% CI 0.49-0.86). These results are in contrast to the phase 3 IMpassion131 trial which found no statistically significant difference in PFS or OS among 651 patients with mTNBC randomized to atezolizumab + paclitaxel vs placebo + paclitaxel (PD-L1-positive population: PFS 6.0 vs 5.7 months, HR 0.82, 95% CI 0.60-1.12; OS 22.1 vs 28.3 months, HR 1.11, 95% CI 0.76-1.62) (Miles et al). The reasons underlying these differences remain unclear and warrant further investigation. Some thoughts raised include lack of information on BRCA status (which may serve as prognostic factor) in IMpassion131, concomitant use of steroids with paclitaxel, and allowance of sufficient long-term follow-up for generation of events. Regardless, these studies suggest chemotherapy backbone is relevant and the regimens utilized in IMpassion130 and KEYNOTE-355 have gained FDA approval in the first-line mTNBC setting.

The phase 3 CLEOPATRA trial has established the regimen of docetaxel + trastuzumab + pertuzumab as standard of care in the first-line setting for metastatic HER2-positive breast cancer with an OS benefit of 16 months compared to docetaxel + trastuzumab + placebo (57.1 vs 40.8 months; HR 0.69, 95% CI 0.58-0.82) with over 8 years of follow-up. PERUSE was a single-arm phase 3b study that investigated the safety and efficacy of trastuzumab + pertuzumab combined with various taxanes (docetaxel, paclitaxel or nab-paclitaxel) among 1426 patients with HER2+ mBC (Miles et al). In the overall population at follow-up of 5.7 years, median PFS and OS were 20.7 and 65.3 months, respectively, and were similar regardless of taxane backbone. Docetaxel was associated with higher incidences of neutropenia and febrile neutropenia. These results support consideration of an alternative taxane combined with trastuzumab + pertuzumab in this setting (for example paclitaxel) in patients who may not be ideal candidates for docetaxel.

In the second-line treatment setting for HER2+ mBC with prior exposure to trastuzumab and taxane, the phase 3 EMILIA study showed improvement in OS with T-DM1 vs capecitabine + lapatinib (mOS 29.9 vs 25.9 months, HR 0.75, 95% CI 0.64-0.88). Ethier et al explored real-world application and outcomes associated with pertuzumab and T-DM1 in the first- and second-line settings respectively, in a population-based, retrospective cohort study in Ontario, Canada. In the pertuzumab cohort, median OS and time on treatment were 43 and 4 months, respectively. In the T-DM1 cohort, median OS and time on treatment were 15 months and 4 months, respectively. Additionally, patients in the T-DM1 cohort who were pertuzumab-naïve appeared to do better, potentially suggesting less responsiveness to subsequent HER2-targeted treatment in the real world setting among those who received prior pertuzumab. Findings from this population study demonstrate inferior outcomes when compared to the pivotal CLEOPATRA and EMILIA trials, and highlight a gap between clinical trial and real-world observations (described by authors as efficacy-effectiveness gap). Potential etiologies for these differences include patient factors, prior therapies and delivery of care models, and convey the importance of recognizing this gap exists and optimizing any modifiable factors as trial data and novel therapies are applied to routine clinical practice.

References:

Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2014;2(4):361-70.

Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020;396(10265):1817-1828.

Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530.

Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732-742.

The seroconversion was highest in patients with CML with 75% and observed in 5/6 (83%) of CML patients receiving imatinib that compare favorably to the total group with 58% of seroconversions. Interestingly patients treated with pegylated interferon also had a a high response with 88% (7/8).

Another recent publication by Harrington et al Br J Hem 2021, Jun 3 ahead or print, confirmed and extending the previous data by evaluating humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 patients with CML. 87.5% patients have a seroconversion and 93.3% developed a T cell response. These responses are seen in contrast to patients with lymphoid hematological malignancies where the responses have been significantly lower.

The main goal of the treatment for chronic phase CML is to stop the progression to more advanced phased of the disease such as blast phase, where treatments are limited and there are no consensus in the treatment approach. In a recent publication by Saxena et al. J Hematol Oncol. 2021 Jun 15 the authors reported the outcomes of patients with BP-CML treated with different regimens that include a combination therapy of tyrosine kinase inhibitor (TKI) with intensive chemotherapy (IC) or hypomethylating agent (HMA) as well as  TKI or IC alone. Response rates were similar between patients treated with IC + TKI and HMA + TKI. When compared to treatment with TKI alone, treatment with IC/HMA + TKI was superior (CRi 57.5% vs 33.9%), as well as higher complete cytogenetic response rate (45% vs 10.7%) and more patients proceeding to ASCT (32.5% vs 10.7%). The results were even better when using a second generation TKI in combination with IC or HMA with a favorable EFS and OS compared to TKI alone.

The seroconversion was highest in patients with CML with 75% and observed in 5/6 (83%) of CML patients receiving imatinib that compare favorably to the total group with 58% of seroconversions. Interestingly patients treated with pegylated interferon also had a a high response with 88% (7/8).

Another recent publication by Harrington et al Br J Hem 2021, Jun 3 ahead or print, confirmed and extending the previous data by evaluating humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 patients with CML. 87.5% patients have a seroconversion and 93.3% developed a T cell response. These responses are seen in contrast to patients with lymphoid hematological malignancies where the responses have been significantly lower.

The main goal of the treatment for chronic phase CML is to stop the progression to more advanced phased of the disease such as blast phase, where treatments are limited and there are no consensus in the treatment approach. In a recent publication by Saxena et al. J Hematol Oncol. 2021 Jun 15 the authors reported the outcomes of patients with BP-CML treated with different regimens that include a combination therapy of tyrosine kinase inhibitor (TKI) with intensive chemotherapy (IC) or hypomethylating agent (HMA) as well as  TKI or IC alone. Response rates were similar between patients treated with IC + TKI and HMA + TKI. When compared to treatment with TKI alone, treatment with IC/HMA + TKI was superior (CRi 57.5% vs 33.9%), as well as higher complete cytogenetic response rate (45% vs 10.7%) and more patients proceeding to ASCT (32.5% vs 10.7%). The results were even better when using a second generation TKI in combination with IC or HMA with a favorable EFS and OS compared to TKI alone.

The seroconversion was highest in patients with CML with 75% and observed in 5/6 (83%) of CML patients receiving imatinib that compare favorably to the total group with 58% of seroconversions. Interestingly patients treated with pegylated interferon also had a a high response with 88% (7/8).

Another recent publication by Harrington et al Br J Hem 2021, Jun 3 ahead or print, confirmed and extending the previous data by evaluating humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 patients with CML. 87.5% patients have a seroconversion and 93.3% developed a T cell response. These responses are seen in contrast to patients with lymphoid hematological malignancies where the responses have been significantly lower.

The main goal of the treatment for chronic phase CML is to stop the progression to more advanced phased of the disease such as blast phase, where treatments are limited and there are no consensus in the treatment approach. In a recent publication by Saxena et al. J Hematol Oncol. 2021 Jun 15 the authors reported the outcomes of patients with BP-CML treated with different regimens that include a combination therapy of tyrosine kinase inhibitor (TKI) with intensive chemotherapy (IC) or hypomethylating agent (HMA) as well as  TKI or IC alone. Response rates were similar between patients treated with IC + TKI and HMA + TKI. When compared to treatment with TKI alone, treatment with IC/HMA + TKI was superior (CRi 57.5% vs 33.9%), as well as higher complete cytogenetic response rate (45% vs 10.7%) and more patients proceeding to ASCT (32.5% vs 10.7%). The results were even better when using a second generation TKI in combination with IC or HMA with a favorable EFS and OS compared to TKI alone.

Key clinical point: Patients with chronic myeloid leukemia (CML) on second-line nilotinib therapy had above-moderate quality of life (QoL) that was influenced by sex, age, education, duration of nilotinib, and existing comorbidities.

Major finding: Patients on second-line nilotinib had above-moderate global health status/QoL scores (mean, 67.70±16.80) and experienced considerable symptoms, particularly fatigue (mean, 28.28±23.74), pain (mean, 21.07±26.16), and insomnia (mean, 22.87±29.20), along with financial difficulties (mean, 52.34±32.15). Female sex (P = .017), age (P = .002), higher level of education (P = .007), duration of nilotinib usage (P = .001), and number of comorbidities (P = .024) were significantly associated with global QoL.

Study details: This study assessed QoL using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire in 121 adult patients with CML who were resistant or intolerant to imatinib and on second-line nilotinib for at least 3 months.

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

Source: Nguyen CTT et al. Qual Life Res. 2021 Jul 14. doi: 10.1007/s11136-021-02952-9.

Key clinical point: Patients with chronic myeloid leukemia (CML) on second-line nilotinib therapy had above-moderate quality of life (QoL) that was influenced by sex, age, education, duration of nilotinib, and existing comorbidities.

Major finding: Patients on second-line nilotinib had above-moderate global health status/QoL scores (mean, 67.70±16.80) and experienced considerable symptoms, particularly fatigue (mean, 28.28±23.74), pain (mean, 21.07±26.16), and insomnia (mean, 22.87±29.20), along with financial difficulties (mean, 52.34±32.15). Female sex (P = .017), age (P = .002), higher level of education (P = .007), duration of nilotinib usage (P = .001), and number of comorbidities (P = .024) were significantly associated with global QoL.

Study details: This study assessed QoL using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire in 121 adult patients with CML who were resistant or intolerant to imatinib and on second-line nilotinib for at least 3 months.

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

Source: Nguyen CTT et al. Qual Life Res. 2021 Jul 14. doi: 10.1007/s11136-021-02952-9.

Key clinical point: Patients with chronic myeloid leukemia (CML) on second-line nilotinib therapy had above-moderate quality of life (QoL) that was influenced by sex, age, education, duration of nilotinib, and existing comorbidities.

Major finding: Patients on second-line nilotinib had above-moderate global health status/QoL scores (mean, 67.70±16.80) and experienced considerable symptoms, particularly fatigue (mean, 28.28±23.74), pain (mean, 21.07±26.16), and insomnia (mean, 22.87±29.20), along with financial difficulties (mean, 52.34±32.15). Female sex (P = .017), age (P = .002), higher level of education (P = .007), duration of nilotinib usage (P = .001), and number of comorbidities (P = .024) were significantly associated with global QoL.

Study details: This study assessed QoL using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire in 121 adult patients with CML who were resistant or intolerant to imatinib and on second-line nilotinib for at least 3 months.

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

Source: Nguyen CTT et al. Qual Life Res. 2021 Jul 14. doi: 10.1007/s11136-021-02952-9.

Key clinical point: Higher body mass index (BMI) and more disturbed sleep were identified as correlates of more severe fatigue, which worsen the quality of life (QoL) in patients with chronic-phase chronic myeloid leukemia (CML-CP) on tyrosine kinase inhibitor (TKI) therapy with self-reported fatigue of at least moderate severity.

Major finding: Higher BMI (P = .01) and more sleep disturbance (P less than .01) were significant correlates of more severe fatigue. Worse fatigue was associated with reduced health-related QoL (P less than .01).

Study details: This study assessed preintervention data from the CBT-TTF trial including 44 adult patients with CML-CP treated with TKIs who self-reported at least moderate fatigue.

Disclosures: This study was funded by the National Cancer Institute. HSL Jim reported consulting for RedHill BioPharma, Janssen Scientific Affairs, and Merck. Other authors declared no conflicts of interest.

Source: Oswald LB et al. Support Care Cancer. 2021 Jul 7. doi: 10.1007/s00520-021-06408-1.

Key clinical point: Higher body mass index (BMI) and more disturbed sleep were identified as correlates of more severe fatigue, which worsen the quality of life (QoL) in patients with chronic-phase chronic myeloid leukemia (CML-CP) on tyrosine kinase inhibitor (TKI) therapy with self-reported fatigue of at least moderate severity.

Major finding: Higher BMI (P = .01) and more sleep disturbance (P less than .01) were significant correlates of more severe fatigue. Worse fatigue was associated with reduced health-related QoL (P less than .01).

Study details: This study assessed preintervention data from the CBT-TTF trial including 44 adult patients with CML-CP treated with TKIs who self-reported at least moderate fatigue.

Disclosures: This study was funded by the National Cancer Institute. HSL Jim reported consulting for RedHill BioPharma, Janssen Scientific Affairs, and Merck. Other authors declared no conflicts of interest.

Source: Oswald LB et al. Support Care Cancer. 2021 Jul 7. doi: 10.1007/s00520-021-06408-1.

Key clinical point: Higher body mass index (BMI) and more disturbed sleep were identified as correlates of more severe fatigue, which worsen the quality of life (QoL) in patients with chronic-phase chronic myeloid leukemia (CML-CP) on tyrosine kinase inhibitor (TKI) therapy with self-reported fatigue of at least moderate severity.

Major finding: Higher BMI (P = .01) and more sleep disturbance (P less than .01) were significant correlates of more severe fatigue. Worse fatigue was associated with reduced health-related QoL (P less than .01).

Study details: This study assessed preintervention data from the CBT-TTF trial including 44 adult patients with CML-CP treated with TKIs who self-reported at least moderate fatigue.

Disclosures: This study was funded by the National Cancer Institute. HSL Jim reported consulting for RedHill BioPharma, Janssen Scientific Affairs, and Merck. Other authors declared no conflicts of interest.

Source: Oswald LB et al. Support Care Cancer. 2021 Jul 7. doi: 10.1007/s00520-021-06408-1.

Key clinical point: Compared with healthy controls, patients with chronic myeloid leukemia (CML) showed significantly higher expression of heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) that correlated with CML disease progression.

Major finding: HNRNPH1 mRNA expression was significantly higher in patients with CML vs healthy controls (P less than .001). HNRNPH1 expression was significantly increased in the accelerated (P less than .05) and blast (P less than .001) phase vs chronic phase of CML.

Study details: Findings are from an analysis of 60 patients with newly diagnosed, untreated CML and 30 healthy donors. Bone marrow mononuclear cells were extracted from patients, and mRNA expression was assessed using quantitative real-time polymerase chain reaction.

Disclosures: This study was partly supported by the Natural Science Foundation of Hebei Province. The authors declared no conflicts of interest.

Source: Liu M et al. Front Oncol. 2021 Jul 6. doi: 10.3389/fonc.2021.682859.

Key clinical point: Compared with healthy controls, patients with chronic myeloid leukemia (CML) showed significantly higher expression of heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) that correlated with CML disease progression.

Major finding: HNRNPH1 mRNA expression was significantly higher in patients with CML vs healthy controls (P less than .001). HNRNPH1 expression was significantly increased in the accelerated (P less than .05) and blast (P less than .001) phase vs chronic phase of CML.

Study details: Findings are from an analysis of 60 patients with newly diagnosed, untreated CML and 30 healthy donors. Bone marrow mononuclear cells were extracted from patients, and mRNA expression was assessed using quantitative real-time polymerase chain reaction.

Disclosures: This study was partly supported by the Natural Science Foundation of Hebei Province. The authors declared no conflicts of interest.

Source: Liu M et al. Front Oncol. 2021 Jul 6. doi: 10.3389/fonc.2021.682859.

Key clinical point: Compared with healthy controls, patients with chronic myeloid leukemia (CML) showed significantly higher expression of heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) that correlated with CML disease progression.

Major finding: HNRNPH1 mRNA expression was significantly higher in patients with CML vs healthy controls (P less than .001). HNRNPH1 expression was significantly increased in the accelerated (P less than .05) and blast (P less than .001) phase vs chronic phase of CML.

Study details: Findings are from an analysis of 60 patients with newly diagnosed, untreated CML and 30 healthy donors. Bone marrow mononuclear cells were extracted from patients, and mRNA expression was assessed using quantitative real-time polymerase chain reaction.

Disclosures: This study was partly supported by the Natural Science Foundation of Hebei Province. The authors declared no conflicts of interest.

Source: Liu M et al. Front Oncol. 2021 Jul 6. doi: 10.3389/fonc.2021.682859.

Key clinical point: The peripheral blood parameters of total white blood cell (WBC) count at least 20×10⁹/L, basophilia, and granulocytic left shift could help identify the need for BCR-ABL1 testing for chronic myeloid leukemia (CML) diagnosis, thereby reducing unnecessary testing, health care costs, and risk of clinically false-positive results.

Major finding: Overall, 92% of patients with newly diagnosed CML had a WBC count of at least 20×10⁹/L, whereas 92% of non-CML patients had a WBC count less than 20×10⁹/L. A positive BCR-ABL1 p210 result was associated with the presence of basophilia (86% sensitivity; 96% specificity), granulocytic left shift with circulating myelocytes and metamyelocytes (95% sensitivity; 94% specificity), and WBC of at least 20×10⁹/L (92% sensitivity; 92% specificity).

Study details: Findings are from a retrospective analysis of 495 patients undergoing first-time testing for p210 BCR-ABL1 on peripheral blood by real-time polymerase chain reaction.

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

Source: Fenu E et al. Int J Lan Hematol. 2021 Jun 29. doi: 10.1111/ijlh.13635.

Key clinical point: The peripheral blood parameters of total white blood cell (WBC) count at least 20×10⁹/L, basophilia, and granulocytic left shift could help identify the need for BCR-ABL1 testing for chronic myeloid leukemia (CML) diagnosis, thereby reducing unnecessary testing, health care costs, and risk of clinically false-positive results.

Major finding: Overall, 92% of patients with newly diagnosed CML had a WBC count of at least 20×10⁹/L, whereas 92% of non-CML patients had a WBC count less than 20×10⁹/L. A positive BCR-ABL1 p210 result was associated with the presence of basophilia (86% sensitivity; 96% specificity), granulocytic left shift with circulating myelocytes and metamyelocytes (95% sensitivity; 94% specificity), and WBC of at least 20×10⁹/L (92% sensitivity; 92% specificity).

Study details: Findings are from a retrospective analysis of 495 patients undergoing first-time testing for p210 BCR-ABL1 on peripheral blood by real-time polymerase chain reaction.

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

Source: Fenu E et al. Int J Lan Hematol. 2021 Jun 29. doi: 10.1111/ijlh.13635.

Key clinical point: The peripheral blood parameters of total white blood cell (WBC) count at least 20×10⁹/L, basophilia, and granulocytic left shift could help identify the need for BCR-ABL1 testing for chronic myeloid leukemia (CML) diagnosis, thereby reducing unnecessary testing, health care costs, and risk of clinically false-positive results.

Major finding: Overall, 92% of patients with newly diagnosed CML had a WBC count of at least 20×10⁹/L, whereas 92% of non-CML patients had a WBC count less than 20×10⁹/L. A positive BCR-ABL1 p210 result was associated with the presence of basophilia (86% sensitivity; 96% specificity), granulocytic left shift with circulating myelocytes and metamyelocytes (95% sensitivity; 94% specificity), and WBC of at least 20×10⁹/L (92% sensitivity; 92% specificity).

Study details: Findings are from a retrospective analysis of 495 patients undergoing first-time testing for p210 BCR-ABL1 on peripheral blood by real-time polymerase chain reaction.

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

Source: Fenu E et al. Int J Lan Hematol. 2021 Jun 29. doi: 10.1111/ijlh.13635.

Key clinical point: Blood cell counts collected up to 5 years before chronic myeloid leukemia (CML) diagnosis could predict BCR-ABL1 test using machine learning methods. Such predictive models may enable early diagnosis of CML, and subsequently, earlier treatment initiation, leading to a better prognosis.

Major finding: The BCR-ABL1 positivity rate was 6.2%. The ability of machine learning models to predict CML diagnosis improved with the usage of blood cell counts closer to the time of diagnosis (at diagnosis: area under the curve [AUC], 0.87-0.96; 6 months to 1-year prediagnosis: AUC, 0.75-0.80; 2-5 years prediagnosis: AUC, 0.59-0.67).

Study details: This study included 1,623 patients with a BCR-ABL1 test and at least 6 consecutive prior years of differential blood cell counts between October 1999 and April 2020 from the Veterans Health Administration database.

Disclosures: No source of funding or author disclosures were reported.

Source: Hauser RG et al. Am J Clin Pathol. 2021 Jun 29. doi: 10.1093/ajcp/aqab086.

Key clinical point: Blood cell counts collected up to 5 years before chronic myeloid leukemia (CML) diagnosis could predict BCR-ABL1 test using machine learning methods. Such predictive models may enable early diagnosis of CML, and subsequently, earlier treatment initiation, leading to a better prognosis.

Major finding: The BCR-ABL1 positivity rate was 6.2%. The ability of machine learning models to predict CML diagnosis improved with the usage of blood cell counts closer to the time of diagnosis (at diagnosis: area under the curve [AUC], 0.87-0.96; 6 months to 1-year prediagnosis: AUC, 0.75-0.80; 2-5 years prediagnosis: AUC, 0.59-0.67).

Study details: This study included 1,623 patients with a BCR-ABL1 test and at least 6 consecutive prior years of differential blood cell counts between October 1999 and April 2020 from the Veterans Health Administration database.

Disclosures: No source of funding or author disclosures were reported.

Source: Hauser RG et al. Am J Clin Pathol. 2021 Jun 29. doi: 10.1093/ajcp/aqab086.

Key clinical point: Blood cell counts collected up to 5 years before chronic myeloid leukemia (CML) diagnosis could predict BCR-ABL1 test using machine learning methods. Such predictive models may enable early diagnosis of CML, and subsequently, earlier treatment initiation, leading to a better prognosis.

Major finding: The BCR-ABL1 positivity rate was 6.2%. The ability of machine learning models to predict CML diagnosis improved with the usage of blood cell counts closer to the time of diagnosis (at diagnosis: area under the curve [AUC], 0.87-0.96; 6 months to 1-year prediagnosis: AUC, 0.75-0.80; 2-5 years prediagnosis: AUC, 0.59-0.67).

Study details: This study included 1,623 patients with a BCR-ABL1 test and at least 6 consecutive prior years of differential blood cell counts between October 1999 and April 2020 from the Veterans Health Administration database.

Disclosures: No source of funding or author disclosures were reported.

Source: Hauser RG et al. Am J Clin Pathol. 2021 Jun 29. doi: 10.1093/ajcp/aqab086.

Key clinical point: Among patients with myeloid blast phase chronic myeloid leukemia (CML-MBP), combination therapy of tyrosine kinase inhibitor (TKI) with intensive chemotherapy (IC) or hypomethylating agent (HMA) resulted in better clinical outcomes vs TKI alone.

Major finding: IC/HMA+TKI vs TKI alone resulted in higher rates of complete remission (CR) or CR with incomplete count recovery (57.5% vs 33.9%), complete cytogenic response (45.0% vs 10.7%), major/deep molecular response (24.2% vs 4.3%;), and more patients proceeding to allogeneic stem cell transplant (32.5% vs 10.7%). In patients receiving the second/third generation TKIs, IC/HMA+TKI led to superior 5-year event-free survival (28% vs 0%) and reduced relapse (44% vs 86%) vs TKI alone (all P less than .05).

Study details: Findings are from a retrospective analysis of 104 patients with CML-MBP receiving frontline treatment based on 4 different approaches, i.e., IC+TKI (n=20), HMA+TKI (n=20), TKI alone (n=56), or IC alone (n=8), between 2000 and 2019.

Disclosures: This study was supported by MD Anderson Cancer Center Support Grant and SPORE. NJ Short reported ties with various pharmaceutical companies. Other authors declared no competing interests.

Source: Saxena K et al. J Hematol Oncol. 2021 Jun 15. doi: 10.1186/s13045-021-01106-1.

Key clinical point: Among patients with myeloid blast phase chronic myeloid leukemia (CML-MBP), combination therapy of tyrosine kinase inhibitor (TKI) with intensive chemotherapy (IC) or hypomethylating agent (HMA) resulted in better clinical outcomes vs TKI alone.

Major finding: IC/HMA+TKI vs TKI alone resulted in higher rates of complete remission (CR) or CR with incomplete count recovery (57.5% vs 33.9%), complete cytogenic response (45.0% vs 10.7%), major/deep molecular response (24.2% vs 4.3%;), and more patients proceeding to allogeneic stem cell transplant (32.5% vs 10.7%). In patients receiving the second/third generation TKIs, IC/HMA+TKI led to superior 5-year event-free survival (28% vs 0%) and reduced relapse (44% vs 86%) vs TKI alone (all P less than .05).

Study details: Findings are from a retrospective analysis of 104 patients with CML-MBP receiving frontline treatment based on 4 different approaches, i.e., IC+TKI (n=20), HMA+TKI (n=20), TKI alone (n=56), or IC alone (n=8), between 2000 and 2019.

Disclosures: This study was supported by MD Anderson Cancer Center Support Grant and SPORE. NJ Short reported ties with various pharmaceutical companies. Other authors declared no competing interests.

Source: Saxena K et al. J Hematol Oncol. 2021 Jun 15. doi: 10.1186/s13045-021-01106-1.

Key clinical point: Among patients with myeloid blast phase chronic myeloid leukemia (CML-MBP), combination therapy of tyrosine kinase inhibitor (TKI) with intensive chemotherapy (IC) or hypomethylating agent (HMA) resulted in better clinical outcomes vs TKI alone.

Major finding: IC/HMA+TKI vs TKI alone resulted in higher rates of complete remission (CR) or CR with incomplete count recovery (57.5% vs 33.9%), complete cytogenic response (45.0% vs 10.7%), major/deep molecular response (24.2% vs 4.3%;), and more patients proceeding to allogeneic stem cell transplant (32.5% vs 10.7%). In patients receiving the second/third generation TKIs, IC/HMA+TKI led to superior 5-year event-free survival (28% vs 0%) and reduced relapse (44% vs 86%) vs TKI alone (all P less than .05).

Study details: Findings are from a retrospective analysis of 104 patients with CML-MBP receiving frontline treatment based on 4 different approaches, i.e., IC+TKI (n=20), HMA+TKI (n=20), TKI alone (n=56), or IC alone (n=8), between 2000 and 2019.

Disclosures: This study was supported by MD Anderson Cancer Center Support Grant and SPORE. NJ Short reported ties with various pharmaceutical companies. Other authors declared no competing interests.

Source: Saxena K et al. J Hematol Oncol. 2021 Jun 15. doi: 10.1186/s13045-021-01106-1.

Key clinical point: Presence of non-breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) mutations in patients with chronic myeloid leukemia (CML) was not associated with clinical outcomes.

Major finding: Non-BCR-ABL1 mutations were observed in 18% of patients with CML at diagnosis and were mostly cleared with TKI therapy, indicating an origin in the Philadelphia chromosome-positive clone. However, no difference was observed in overall survival, progression-free survival, failure-free survival, and adverse events between patients with vs without non-BCR-ABL1 mutations.

Study details: Findings are from next-generation sequencing analysis of BCR-ABL1 kinase domain and 18 myeloid neoplasm-associated genes in 49 patients with de novo chronic phase-CML and 6 healthy controls.

Disclosures: This study was supported by grants from the Ministry of Health of the Czech Republic, the Ministry of Education, and Bristol-Myers Squibb. D Zackova and J Mayer reported ties with various pharmaceutical companies including Bristol-Myers Squibb. Other authors declared no competing interests.

Source: Romzova M et al. Br J Haematol. 2021 Jul 1. doi: 10.1111/bjh.17659.

Key clinical point: Presence of non-breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) mutations in patients with chronic myeloid leukemia (CML) was not associated with clinical outcomes.

Major finding: Non-BCR-ABL1 mutations were observed in 18% of patients with CML at diagnosis and were mostly cleared with TKI therapy, indicating an origin in the Philadelphia chromosome-positive clone. However, no difference was observed in overall survival, progression-free survival, failure-free survival, and adverse events between patients with vs without non-BCR-ABL1 mutations.

Study details: Findings are from next-generation sequencing analysis of BCR-ABL1 kinase domain and 18 myeloid neoplasm-associated genes in 49 patients with de novo chronic phase-CML and 6 healthy controls.

Disclosures: This study was supported by grants from the Ministry of Health of the Czech Republic, the Ministry of Education, and Bristol-Myers Squibb. D Zackova and J Mayer reported ties with various pharmaceutical companies including Bristol-Myers Squibb. Other authors declared no competing interests.

Source: Romzova M et al. Br J Haematol. 2021 Jul 1. doi: 10.1111/bjh.17659.

Key clinical point: Presence of non-breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) mutations in patients with chronic myeloid leukemia (CML) was not associated with clinical outcomes.

Major finding: Non-BCR-ABL1 mutations were observed in 18% of patients with CML at diagnosis and were mostly cleared with TKI therapy, indicating an origin in the Philadelphia chromosome-positive clone. However, no difference was observed in overall survival, progression-free survival, failure-free survival, and adverse events between patients with vs without non-BCR-ABL1 mutations.

Study details: Findings are from next-generation sequencing analysis of BCR-ABL1 kinase domain and 18 myeloid neoplasm-associated genes in 49 patients with de novo chronic phase-CML and 6 healthy controls.

Disclosures: This study was supported by grants from the Ministry of Health of the Czech Republic, the Ministry of Education, and Bristol-Myers Squibb. D Zackova and J Mayer reported ties with various pharmaceutical companies including Bristol-Myers Squibb. Other authors declared no competing interests.

Source: Romzova M et al. Br J Haematol. 2021 Jul 1. doi: 10.1111/bjh.17659.