The current COVID-19 pandemic has afflicted over 44 million individuals across the planet and been responsible for over 1 million deaths, particularly in high-risk populations. As a result of the overall advanced age, frailty and pre-existing comorbidities of patients with MDS, SARS-Cov2 was feared to be particularly dangerous in this patient population. A recent study by Mossuto et al describes the outcomes of patients with MDS with SARS-CoV-2 infection during the Coronavirus outbreak in Italy. Among a total of 5326 patients with MDS followed during the study period, 63 (1.18%) had confirmed SARS-CoV-2 infection. With a median age of 73 years, the mortality rate among these patients was 52% compared to that of the non-MDS population (24%), and was particularly high on male MDS patients (73% of total deaths). Respiratory failure was the cause of death in all the MDS patients with ARDS in 50% of deceased patients, and with majority of patients who were able to recover having lower risk IPSS-R categories. Interestingly, no differences in mortality or severity of infection were observed based on the type of therapy received for their MDS. These findings are not surprising given the underlying inflammation and immunosuppression in patients with MDS. Until the development of COVID-19 vaccines has been completed, identification of high-risk populations and specific guidelines for the management of SARS-CoV-2 infection in patients with MDS remains of paramount importance.

Clonal hematopoiesis is a known cardiovascular risk factor which has been associated with increased risk of cardiac and cerebrovascular events. Recent studies have also associated MDS with higher than expected cardiovascular comorbidities and cardiovascular-related deaths. In accordance to prior publications by Naqvi et al, a recent study by Faber et al retrospectively evaluated 236 MDS patients and studied the associations of somatic mutations with cardiovascular risk. Overall, the authors observed that 27% of patients in their study population developed vascular event, and that ASXL1 mutations were predictive of vascular disease by multivariate analysis (with an odds ratio of 4.2). This data further supports the biological connection between comorbidities and hematopoietic clonal disorders, the role of inflammaging and the need to maximize cardiovascular risk factor care in patients with MDS and develop specific therapies targeting both the disease biology and the underlying mechanisms leading to increased cardiovascular risk.

Guillermo Montalban Bravo, MD
Assistant Professor, Department of Leukemia, Division of Cancer Medicine
MD Anderson Cancer Center, Houston, TX

The current COVID-19 pandemic has afflicted over 44 million individuals across the planet and been responsible for over 1 million deaths, particularly in high-risk populations. As a result of the overall advanced age, frailty and pre-existing comorbidities of patients with MDS, SARS-Cov2 was feared to be particularly dangerous in this patient population. A recent study by Mossuto et al describes the outcomes of patients with MDS with SARS-CoV-2 infection during the Coronavirus outbreak in Italy. Among a total of 5326 patients with MDS followed during the study period, 63 (1.18%) had confirmed SARS-CoV-2 infection. With a median age of 73 years, the mortality rate among these patients was 52% compared to that of the non-MDS population (24%), and was particularly high on male MDS patients (73% of total deaths). Respiratory failure was the cause of death in all the MDS patients with ARDS in 50% of deceased patients, and with majority of patients who were able to recover having lower risk IPSS-R categories. Interestingly, no differences in mortality or severity of infection were observed based on the type of therapy received for their MDS. These findings are not surprising given the underlying inflammation and immunosuppression in patients with MDS. Until the development of COVID-19 vaccines has been completed, identification of high-risk populations and specific guidelines for the management of SARS-CoV-2 infection in patients with MDS remains of paramount importance.

Clonal hematopoiesis is a known cardiovascular risk factor which has been associated with increased risk of cardiac and cerebrovascular events. Recent studies have also associated MDS with higher than expected cardiovascular comorbidities and cardiovascular-related deaths. In accordance to prior publications by Naqvi et al, a recent study by Faber et al retrospectively evaluated 236 MDS patients and studied the associations of somatic mutations with cardiovascular risk. Overall, the authors observed that 27% of patients in their study population developed vascular event, and that ASXL1 mutations were predictive of vascular disease by multivariate analysis (with an odds ratio of 4.2). This data further supports the biological connection between comorbidities and hematopoietic clonal disorders, the role of inflammaging and the need to maximize cardiovascular risk factor care in patients with MDS and develop specific therapies targeting both the disease biology and the underlying mechanisms leading to increased cardiovascular risk.

Guillermo Montalban Bravo, MD
Assistant Professor, Department of Leukemia, Division of Cancer Medicine
MD Anderson Cancer Center, Houston, TX

The current COVID-19 pandemic has afflicted over 44 million individuals across the planet and been responsible for over 1 million deaths, particularly in high-risk populations. As a result of the overall advanced age, frailty and pre-existing comorbidities of patients with MDS, SARS-Cov2 was feared to be particularly dangerous in this patient population. A recent study by Mossuto et al describes the outcomes of patients with MDS with SARS-CoV-2 infection during the Coronavirus outbreak in Italy. Among a total of 5326 patients with MDS followed during the study period, 63 (1.18%) had confirmed SARS-CoV-2 infection. With a median age of 73 years, the mortality rate among these patients was 52% compared to that of the non-MDS population (24%), and was particularly high on male MDS patients (73% of total deaths). Respiratory failure was the cause of death in all the MDS patients with ARDS in 50% of deceased patients, and with majority of patients who were able to recover having lower risk IPSS-R categories. Interestingly, no differences in mortality or severity of infection were observed based on the type of therapy received for their MDS. These findings are not surprising given the underlying inflammation and immunosuppression in patients with MDS. Until the development of COVID-19 vaccines has been completed, identification of high-risk populations and specific guidelines for the management of SARS-CoV-2 infection in patients with MDS remains of paramount importance.

Clonal hematopoiesis is a known cardiovascular risk factor which has been associated with increased risk of cardiac and cerebrovascular events. Recent studies have also associated MDS with higher than expected cardiovascular comorbidities and cardiovascular-related deaths. In accordance to prior publications by Naqvi et al, a recent study by Faber et al retrospectively evaluated 236 MDS patients and studied the associations of somatic mutations with cardiovascular risk. Overall, the authors observed that 27% of patients in their study population developed vascular event, and that ASXL1 mutations were predictive of vascular disease by multivariate analysis (with an odds ratio of 4.2). This data further supports the biological connection between comorbidities and hematopoietic clonal disorders, the role of inflammaging and the need to maximize cardiovascular risk factor care in patients with MDS and develop specific therapies targeting both the disease biology and the underlying mechanisms leading to increased cardiovascular risk.

Guillermo Montalban Bravo, MD
Assistant Professor, Department of Leukemia, Division of Cancer Medicine
MD Anderson Cancer Center, Houston, TX

Key clinical point: Gene mutations involving ASXL1 were significantly associated with increased risk of vascular events in adults with myelodysplastic syndrome, but Trisomy 8 appeared to have a protective effect.

Major finding: Overall, the incidence of vascular disease in the study population was 27%; mutations in the ASXL1 in particular were significant predictors of vascular disease in multivariate analysis (odds ratio 4.2); however, both elevated ferritin and Trisomy 8 were significantly associated with a lower risk of vascular disease in low-risk MDS patients (P = .043 and P = .036, respectively).

Study details: The data come from a retrospective analysis of 236 MDS patients aged 18 years and older who were seen and treated at a single center between 2010 and 2018.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.  

Citation: Faber MG et al. eJHaem. 2020 Sept 28. doi: 10.1002/jha2.101.

Key clinical point: Gene mutations involving ASXL1 were significantly associated with increased risk of vascular events in adults with myelodysplastic syndrome, but Trisomy 8 appeared to have a protective effect.

Major finding: Overall, the incidence of vascular disease in the study population was 27%; mutations in the ASXL1 in particular were significant predictors of vascular disease in multivariate analysis (odds ratio 4.2); however, both elevated ferritin and Trisomy 8 were significantly associated with a lower risk of vascular disease in low-risk MDS patients (P = .043 and P = .036, respectively).

Study details: The data come from a retrospective analysis of 236 MDS patients aged 18 years and older who were seen and treated at a single center between 2010 and 2018.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.  

Citation: Faber MG et al. eJHaem. 2020 Sept 28. doi: 10.1002/jha2.101.

Key clinical point: Gene mutations involving ASXL1 were significantly associated with increased risk of vascular events in adults with myelodysplastic syndrome, but Trisomy 8 appeared to have a protective effect.

Major finding: Overall, the incidence of vascular disease in the study population was 27%; mutations in the ASXL1 in particular were significant predictors of vascular disease in multivariate analysis (odds ratio 4.2); however, both elevated ferritin and Trisomy 8 were significantly associated with a lower risk of vascular disease in low-risk MDS patients (P = .043 and P = .036, respectively).

Study details: The data come from a retrospective analysis of 236 MDS patients aged 18 years and older who were seen and treated at a single center between 2010 and 2018.

Disclosures: The study received no outside funding. The researchers had no financial conflicts to disclose.  

Citation: Faber MG et al. eJHaem. 2020 Sept 28. doi: 10.1002/jha2.101.

Key clinical point: Myelodysplastic syndrome patients who had a slower luspatercept apparent clearance (CL/F) were more likely to achieve erythroid responses, suggesting potential as an early efficacy marker.

Major finding: Luspatercept given over a dose range of 0.125 mg/kg-1.75 mg/kg yielded linear and time-invariant pharmacokinetics when given to MDS patients with anemia subcutaneously once every 3 weeks; the odds of transfusion independence at a minimum of 8 weeks increased with time-averaged exposure and plateaued at 1.0 mg/kg-1.75 mg/kg.

Study details: The data come from a review of several studies including 260 adults with anemia caused by myelodysplastic syndromes.

Disclosures: The studies in the review were funded by Bristol Myers Squibb or Acceleron. Lead author Dr. Chen and several coauthors are employees of Bristol Myers Squibb.

Citation: Chen N et al. CPT Pharmacometrics Syst Pharmacol. 2020 June 30. doi: 10.1002/psp4.12521.

Key clinical point: Myelodysplastic syndrome patients who had a slower luspatercept apparent clearance (CL/F) were more likely to achieve erythroid responses, suggesting potential as an early efficacy marker.

Major finding: Luspatercept given over a dose range of 0.125 mg/kg-1.75 mg/kg yielded linear and time-invariant pharmacokinetics when given to MDS patients with anemia subcutaneously once every 3 weeks; the odds of transfusion independence at a minimum of 8 weeks increased with time-averaged exposure and plateaued at 1.0 mg/kg-1.75 mg/kg.

Study details: The data come from a review of several studies including 260 adults with anemia caused by myelodysplastic syndromes.

Disclosures: The studies in the review were funded by Bristol Myers Squibb or Acceleron. Lead author Dr. Chen and several coauthors are employees of Bristol Myers Squibb.

Citation: Chen N et al. CPT Pharmacometrics Syst Pharmacol. 2020 June 30. doi: 10.1002/psp4.12521.

Key clinical point: Myelodysplastic syndrome patients who had a slower luspatercept apparent clearance (CL/F) were more likely to achieve erythroid responses, suggesting potential as an early efficacy marker.

Major finding: Luspatercept given over a dose range of 0.125 mg/kg-1.75 mg/kg yielded linear and time-invariant pharmacokinetics when given to MDS patients with anemia subcutaneously once every 3 weeks; the odds of transfusion independence at a minimum of 8 weeks increased with time-averaged exposure and plateaued at 1.0 mg/kg-1.75 mg/kg.

Study details: The data come from a review of several studies including 260 adults with anemia caused by myelodysplastic syndromes.

Disclosures: The studies in the review were funded by Bristol Myers Squibb or Acceleron. Lead author Dr. Chen and several coauthors are employees of Bristol Myers Squibb.

Citation: Chen N et al. CPT Pharmacometrics Syst Pharmacol. 2020 June 30. doi: 10.1002/psp4.12521.

Key clinical point: Approximately half of transfusion-dependent MDS patients said they had not discussed ways to reduce the need for transfusions with their doctors and 74% said there were no alternatives to blood transfusions.

Major finding: Among adults with MDS, those with disease duration less than 5 years cited transfusion reactions as their greatest concern; those with longer disease duration cited iron overload. However, a majority of 71% of the patients ranked their quality of life as good or excellent. MDS physicians reported that they would be most likely to offer blood transfusions as primary therapy to patients who were older than 80 years, frail, had lower risk MDS, or had other significant comorbidities.

Study details: The data come from a pair of cross-sectional surveys including 157 myelodysplastic syndrome (MDS) patients and 109 MDS physicians.

Disclosures: The study was supported by the Aplastic Anemia and MDS International Foundation through a grant from Celgene. Lead author Dr. King was supported in part by The Maren Research Award Scholarship through the University of Florida.

Citation: King D et al. Leuk Res. 2020 July 15. doi: 10.1016/j.leukres.2020.106425.

Key clinical point: Approximately half of transfusion-dependent MDS patients said they had not discussed ways to reduce the need for transfusions with their doctors and 74% said there were no alternatives to blood transfusions.

Major finding: Among adults with MDS, those with disease duration less than 5 years cited transfusion reactions as their greatest concern; those with longer disease duration cited iron overload. However, a majority of 71% of the patients ranked their quality of life as good or excellent. MDS physicians reported that they would be most likely to offer blood transfusions as primary therapy to patients who were older than 80 years, frail, had lower risk MDS, or had other significant comorbidities.

Study details: The data come from a pair of cross-sectional surveys including 157 myelodysplastic syndrome (MDS) patients and 109 MDS physicians.

Disclosures: The study was supported by the Aplastic Anemia and MDS International Foundation through a grant from Celgene. Lead author Dr. King was supported in part by The Maren Research Award Scholarship through the University of Florida.

Citation: King D et al. Leuk Res. 2020 July 15. doi: 10.1016/j.leukres.2020.106425.

Key clinical point: Approximately half of transfusion-dependent MDS patients said they had not discussed ways to reduce the need for transfusions with their doctors and 74% said there were no alternatives to blood transfusions.

Major finding: Among adults with MDS, those with disease duration less than 5 years cited transfusion reactions as their greatest concern; those with longer disease duration cited iron overload. However, a majority of 71% of the patients ranked their quality of life as good or excellent. MDS physicians reported that they would be most likely to offer blood transfusions as primary therapy to patients who were older than 80 years, frail, had lower risk MDS, or had other significant comorbidities.

Study details: The data come from a pair of cross-sectional surveys including 157 myelodysplastic syndrome (MDS) patients and 109 MDS physicians.

Disclosures: The study was supported by the Aplastic Anemia and MDS International Foundation through a grant from Celgene. Lead author Dr. King was supported in part by The Maren Research Award Scholarship through the University of Florida.

Citation: King D et al. Leuk Res. 2020 July 15. doi: 10.1016/j.leukres.2020.106425.

Key clinical point: Bronchoscopy was safe for most patients with malignant hematologic disorders with careful monitoring and use of sedatives, particularly midazolam.

Major finding: A total of 12 out of 272 patients (3.8%) experienced prolonged oxygen desaturation; 7 of these recovered and 5 died from lung lesion deterioration. However, midazolam reduced the risk of prolonged oxygen desaturation in the study population.

Study details: The data come from a review of 316 bronchoscopies in 282 adults with malignant hematologic disorders and pulmonary infiltrates who were treated at a single center.

Disclosures: Lead author Dr. Uruga disclosed grant support from Okinaka Memorial Institute for Medical Research.

Citation: Uruga H et al. BMC Pulm Med. 2020 Sep 11. doi: 10.1186/s12890-020-01283-8.

Key clinical point: Bronchoscopy was safe for most patients with malignant hematologic disorders with careful monitoring and use of sedatives, particularly midazolam.

Major finding: A total of 12 out of 272 patients (3.8%) experienced prolonged oxygen desaturation; 7 of these recovered and 5 died from lung lesion deterioration. However, midazolam reduced the risk of prolonged oxygen desaturation in the study population.

Study details: The data come from a review of 316 bronchoscopies in 282 adults with malignant hematologic disorders and pulmonary infiltrates who were treated at a single center.

Disclosures: Lead author Dr. Uruga disclosed grant support from Okinaka Memorial Institute for Medical Research.

Citation: Uruga H et al. BMC Pulm Med. 2020 Sep 11. doi: 10.1186/s12890-020-01283-8.

Key clinical point: Bronchoscopy was safe for most patients with malignant hematologic disorders with careful monitoring and use of sedatives, particularly midazolam.

Major finding: A total of 12 out of 272 patients (3.8%) experienced prolonged oxygen desaturation; 7 of these recovered and 5 died from lung lesion deterioration. However, midazolam reduced the risk of prolonged oxygen desaturation in the study population.

Study details: The data come from a review of 316 bronchoscopies in 282 adults with malignant hematologic disorders and pulmonary infiltrates who were treated at a single center.

Disclosures: Lead author Dr. Uruga disclosed grant support from Okinaka Memorial Institute for Medical Research.

Citation: Uruga H et al. BMC Pulm Med. 2020 Sep 11. doi: 10.1186/s12890-020-01283-8.

Key clinical point: Adults with end-stage renal disease who underwent dialysis for at least six months were at significantly increased risk for MDS compared with healthy controls.

Major finding: Patients with chronic renal failure who underwent dialysis were significantly more likely to develop myelodysplastic syndrome compared to healthy controls (subdistribution hazard ratio 1.60); older age also was significantly associated with increased MDS risk (sHR 1.03).

Study details: The data come from a study of 74,712 adults with chronic renal failure diagnoses between 1997 and 2013 who underwent dialysis, and matched controls. Participants were follow from index date to the first occurrence of MDS, withdrawal from the NHI program, or the last day of 2013.

Disclosures: The study used the National Health Insurance Research Database established by the National Health Research Institutes with the authorization of the Bureau of National Health Insurance, Ministry of Health and Welfare of Taiwan. The researchers had no financial conflicts to disclose.

Citation: Chang M-Y et al. Sci Rep. 2020 Sept 23. doi: 10.1038/s41598-020-72568-5.

Key clinical point: Adults with end-stage renal disease who underwent dialysis for at least six months were at significantly increased risk for MDS compared with healthy controls.

Major finding: Patients with chronic renal failure who underwent dialysis were significantly more likely to develop myelodysplastic syndrome compared to healthy controls (subdistribution hazard ratio 1.60); older age also was significantly associated with increased MDS risk (sHR 1.03).

Study details: The data come from a study of 74,712 adults with chronic renal failure diagnoses between 1997 and 2013 who underwent dialysis, and matched controls. Participants were follow from index date to the first occurrence of MDS, withdrawal from the NHI program, or the last day of 2013.

Disclosures: The study used the National Health Insurance Research Database established by the National Health Research Institutes with the authorization of the Bureau of National Health Insurance, Ministry of Health and Welfare of Taiwan. The researchers had no financial conflicts to disclose.

Citation: Chang M-Y et al. Sci Rep. 2020 Sept 23. doi: 10.1038/s41598-020-72568-5.

Key clinical point: Adults with end-stage renal disease who underwent dialysis for at least six months were at significantly increased risk for MDS compared with healthy controls.

Major finding: Patients with chronic renal failure who underwent dialysis were significantly more likely to develop myelodysplastic syndrome compared to healthy controls (subdistribution hazard ratio 1.60); older age also was significantly associated with increased MDS risk (sHR 1.03).

Study details: The data come from a study of 74,712 adults with chronic renal failure diagnoses between 1997 and 2013 who underwent dialysis, and matched controls. Participants were follow from index date to the first occurrence of MDS, withdrawal from the NHI program, or the last day of 2013.

Disclosures: The study used the National Health Insurance Research Database established by the National Health Research Institutes with the authorization of the Bureau of National Health Insurance, Ministry of Health and Welfare of Taiwan. The researchers had no financial conflicts to disclose.

Citation: Chang M-Y et al. Sci Rep. 2020 Sept 23. doi: 10.1038/s41598-020-72568-5.

The days of using chemotherapy to treat Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) may be numbered.

In a phase 2 trial, upfront chemotherapy-free induction/consolidation with the tyrosine kinase inhibitor dasatinib (Sprycel) and the bispecific T-cell engager antibody blinatumomab (Blincyto) yielded high rates of molecular response, “impressive” survival at 18 months, and few toxic effects of grade 3 or higher, say researchers.

With this approach, “60% of adult Ph+ ALL patients, of all ages, can obtain a molecular response, and this percent can increase further with more cycles of blinatumomab,” lead researcher Robin Foà, MD, from Sapienza University of Rome, said in an interview.

“The rates of disease-free survival and overall survival at 18 months are highly favorable, and the protocol is associated with limited toxicity,” Dr. Foà added.

“I see this chemo-free approach becoming a realistic approach for a substantial proportion of adult Ph+ ALL patients, particularly for the older patients, keeping in mind that the incidence of Ph+ ALL increases with age,” Dr. Foà said.

The results of the study were published Oct. 22 in the New England Journal of Medicine.
 

‘Innovative’ and ‘highly successful’

This “innovative” chemotherapy-free approach proved “highly successful” with “surprisingly” few toxic effects, Dieter Hoelzer, MD, PhD, University of Frankfurt (Germany), wrote in a linked editorial.

The Italian GIMEMA LAL2116 D-ALBA trial enrolled 63 adults (median age, 54 years; range, 24-82 years) with newly diagnosed Ph+ ALL. All patients received a glucocorticoid for 31 days beginning 7 days before starting treatment with dasatinib.

Dasatinib (140 mg once daily) induction therapy lasted 85 days. All patients who completed the induction phase received blinatumomab (28 mcg/d) consolidation therapy. Dexamethasone (20 mg) was administered before each blinatumomab cycle. To prevent central nervous system adverse events, levetiracetam (500 mg twice daily) was administered.

All but two patients completed dasatinib induction. One was a 73-year-old woman who withdrew from the trial because of toxic effects after 10 days of dasatinib treatment. She later died of pneumonia. The other was an 82-year-old woman who had a complete hematologic response but left the trial because of pneumonia and pneumonitis.

At the end of the induction phase, 98% of the patients (62 of 63) had a complete hematologic response, including the patient with a complete hematologic response who withdrew; 29% (17 of 59 patients) had a molecular response.

Of the 61 patients who completed the induction phase, 58 received one cycle of blinatumomab, 56 received two cycles, 45 received three cycles, 37 received four cycles, and 29 received five cycles. At the end of the second blinatumomab cycle, 60% of the patients (33 of 55 patients) had a molecular response.

The percentage of patients with a molecular response increased further after receiving additional cycles of blinatumomab – to 70% (28 of 40 patients) after the third cycle, 81% (29 of 36 patients) after the fourth cycle, and 72% (21 of 29 patients) after the fifth cycle.

At a median follow-up of 18 months, overall survival was 95%, and disease-free survival was 88%.

There were no significant differences in DFS between patients with p190-kd fusion protein (85%) and those with p210-kd fusion protein (95%). However, DFS was lower in patients with IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both).

ABL1 mutations were present in six patients who had increased minimal residual disease during induction therapy. All these mutations were cleared by blinatumomab.

There were six relapses, of which three were hematologic. One occurred in a patient with a major protocol violation (a delay of more than 2 months in receiving blinatumomab), one occurred after 12 months in the patient who discontinued the trial after receiving dasatinib for 12 days, and one occurred in a patient after the second cycle of blinatumomab.

A total of 21 adverse events of grade 3 or higher were noted. They included cytomegalovirus reactivation or infection in six patients; neutropenia in four patients; persistent fever in two patients; and pleural effusion, pulmonary hypertension, and a neurologic disorder in one patient each.

Of the 24 patients who received a stem-cell allograft, two died, but only one death was related to transplant (4%).

The very low nonrelapse mortality among patients who underwent transplant during remission is “remarkable,” Dr. Hoelzer wrote. It suggests that toxicity from induction chemotherapy puts the patient at risk for toxic effects and death from subsequent stem-cell transplant – “a consequence that is avoided with targeted therapy.”
 

Unanswered questions

“Will the excellent outcomes be preserved with longer follow-up? The answer is probably yes, given that the majority of relapses in ALL occur within the first 1.5 to 2.0 years after the initiation of treatment,” Dr. Hoelzer wrote.

He said other outstanding questions include whether long-term outcomes will differ between patients who undergo transplant and those who do not; whether ABL1 mutations emerge; whether minimal residual disease recurs with longer follow-up; and whether this treatment approach can be used for patients with other subtypes of ALL, such as Ph-negative, B-lineage ALL, or even T-cell ALL.

“If these promising trial results hold, chemotherapy-free induction without the immediate and long-term toxic effects of intensive chemotherapy regimens could also be used in adolescents and, finally, in children. These questions will need to be addressed with longer follow-up and large, prospective trials,” Dr. Hoelzer concluded.

The study was supported by grants from the Italian Association for Cancer Research and Sapienza University of Rome.

A version of this article originally appeared on Medscape.com

The days of using chemotherapy to treat Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) may be numbered.

In a phase 2 trial, upfront chemotherapy-free induction/consolidation with the tyrosine kinase inhibitor dasatinib (Sprycel) and the bispecific T-cell engager antibody blinatumomab (Blincyto) yielded high rates of molecular response, “impressive” survival at 18 months, and few toxic effects of grade 3 or higher, say researchers.

With this approach, “60% of adult Ph+ ALL patients, of all ages, can obtain a molecular response, and this percent can increase further with more cycles of blinatumomab,” lead researcher Robin Foà, MD, from Sapienza University of Rome, said in an interview.

“The rates of disease-free survival and overall survival at 18 months are highly favorable, and the protocol is associated with limited toxicity,” Dr. Foà added.

“I see this chemo-free approach becoming a realistic approach for a substantial proportion of adult Ph+ ALL patients, particularly for the older patients, keeping in mind that the incidence of Ph+ ALL increases with age,” Dr. Foà said.

The results of the study were published Oct. 22 in the New England Journal of Medicine.
 

‘Innovative’ and ‘highly successful’

This “innovative” chemotherapy-free approach proved “highly successful” with “surprisingly” few toxic effects, Dieter Hoelzer, MD, PhD, University of Frankfurt (Germany), wrote in a linked editorial.

The Italian GIMEMA LAL2116 D-ALBA trial enrolled 63 adults (median age, 54 years; range, 24-82 years) with newly diagnosed Ph+ ALL. All patients received a glucocorticoid for 31 days beginning 7 days before starting treatment with dasatinib.

Dasatinib (140 mg once daily) induction therapy lasted 85 days. All patients who completed the induction phase received blinatumomab (28 mcg/d) consolidation therapy. Dexamethasone (20 mg) was administered before each blinatumomab cycle. To prevent central nervous system adverse events, levetiracetam (500 mg twice daily) was administered.

All but two patients completed dasatinib induction. One was a 73-year-old woman who withdrew from the trial because of toxic effects after 10 days of dasatinib treatment. She later died of pneumonia. The other was an 82-year-old woman who had a complete hematologic response but left the trial because of pneumonia and pneumonitis.

At the end of the induction phase, 98% of the patients (62 of 63) had a complete hematologic response, including the patient with a complete hematologic response who withdrew; 29% (17 of 59 patients) had a molecular response.

Of the 61 patients who completed the induction phase, 58 received one cycle of blinatumomab, 56 received two cycles, 45 received three cycles, 37 received four cycles, and 29 received five cycles. At the end of the second blinatumomab cycle, 60% of the patients (33 of 55 patients) had a molecular response.

The percentage of patients with a molecular response increased further after receiving additional cycles of blinatumomab – to 70% (28 of 40 patients) after the third cycle, 81% (29 of 36 patients) after the fourth cycle, and 72% (21 of 29 patients) after the fifth cycle.

At a median follow-up of 18 months, overall survival was 95%, and disease-free survival was 88%.

There were no significant differences in DFS between patients with p190-kd fusion protein (85%) and those with p210-kd fusion protein (95%). However, DFS was lower in patients with IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both).

ABL1 mutations were present in six patients who had increased minimal residual disease during induction therapy. All these mutations were cleared by blinatumomab.

There were six relapses, of which three were hematologic. One occurred in a patient with a major protocol violation (a delay of more than 2 months in receiving blinatumomab), one occurred after 12 months in the patient who discontinued the trial after receiving dasatinib for 12 days, and one occurred in a patient after the second cycle of blinatumomab.

A total of 21 adverse events of grade 3 or higher were noted. They included cytomegalovirus reactivation or infection in six patients; neutropenia in four patients; persistent fever in two patients; and pleural effusion, pulmonary hypertension, and a neurologic disorder in one patient each.

Of the 24 patients who received a stem-cell allograft, two died, but only one death was related to transplant (4%).

The very low nonrelapse mortality among patients who underwent transplant during remission is “remarkable,” Dr. Hoelzer wrote. It suggests that toxicity from induction chemotherapy puts the patient at risk for toxic effects and death from subsequent stem-cell transplant – “a consequence that is avoided with targeted therapy.”
 

Unanswered questions

“Will the excellent outcomes be preserved with longer follow-up? The answer is probably yes, given that the majority of relapses in ALL occur within the first 1.5 to 2.0 years after the initiation of treatment,” Dr. Hoelzer wrote.

He said other outstanding questions include whether long-term outcomes will differ between patients who undergo transplant and those who do not; whether ABL1 mutations emerge; whether minimal residual disease recurs with longer follow-up; and whether this treatment approach can be used for patients with other subtypes of ALL, such as Ph-negative, B-lineage ALL, or even T-cell ALL.

“If these promising trial results hold, chemotherapy-free induction without the immediate and long-term toxic effects of intensive chemotherapy regimens could also be used in adolescents and, finally, in children. These questions will need to be addressed with longer follow-up and large, prospective trials,” Dr. Hoelzer concluded.

The study was supported by grants from the Italian Association for Cancer Research and Sapienza University of Rome.

A version of this article originally appeared on Medscape.com

The days of using chemotherapy to treat Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) may be numbered.

In a phase 2 trial, upfront chemotherapy-free induction/consolidation with the tyrosine kinase inhibitor dasatinib (Sprycel) and the bispecific T-cell engager antibody blinatumomab (Blincyto) yielded high rates of molecular response, “impressive” survival at 18 months, and few toxic effects of grade 3 or higher, say researchers.

With this approach, “60% of adult Ph+ ALL patients, of all ages, can obtain a molecular response, and this percent can increase further with more cycles of blinatumomab,” lead researcher Robin Foà, MD, from Sapienza University of Rome, said in an interview.

“The rates of disease-free survival and overall survival at 18 months are highly favorable, and the protocol is associated with limited toxicity,” Dr. Foà added.

“I see this chemo-free approach becoming a realistic approach for a substantial proportion of adult Ph+ ALL patients, particularly for the older patients, keeping in mind that the incidence of Ph+ ALL increases with age,” Dr. Foà said.

The results of the study were published Oct. 22 in the New England Journal of Medicine.
 

‘Innovative’ and ‘highly successful’

This “innovative” chemotherapy-free approach proved “highly successful” with “surprisingly” few toxic effects, Dieter Hoelzer, MD, PhD, University of Frankfurt (Germany), wrote in a linked editorial.

The Italian GIMEMA LAL2116 D-ALBA trial enrolled 63 adults (median age, 54 years; range, 24-82 years) with newly diagnosed Ph+ ALL. All patients received a glucocorticoid for 31 days beginning 7 days before starting treatment with dasatinib.

Dasatinib (140 mg once daily) induction therapy lasted 85 days. All patients who completed the induction phase received blinatumomab (28 mcg/d) consolidation therapy. Dexamethasone (20 mg) was administered before each blinatumomab cycle. To prevent central nervous system adverse events, levetiracetam (500 mg twice daily) was administered.

All but two patients completed dasatinib induction. One was a 73-year-old woman who withdrew from the trial because of toxic effects after 10 days of dasatinib treatment. She later died of pneumonia. The other was an 82-year-old woman who had a complete hematologic response but left the trial because of pneumonia and pneumonitis.

At the end of the induction phase, 98% of the patients (62 of 63) had a complete hematologic response, including the patient with a complete hematologic response who withdrew; 29% (17 of 59 patients) had a molecular response.

Of the 61 patients who completed the induction phase, 58 received one cycle of blinatumomab, 56 received two cycles, 45 received three cycles, 37 received four cycles, and 29 received five cycles. At the end of the second blinatumomab cycle, 60% of the patients (33 of 55 patients) had a molecular response.

The percentage of patients with a molecular response increased further after receiving additional cycles of blinatumomab – to 70% (28 of 40 patients) after the third cycle, 81% (29 of 36 patients) after the fourth cycle, and 72% (21 of 29 patients) after the fifth cycle.

At a median follow-up of 18 months, overall survival was 95%, and disease-free survival was 88%.

There were no significant differences in DFS between patients with p190-kd fusion protein (85%) and those with p210-kd fusion protein (95%). However, DFS was lower in patients with IKZF1 deletion plus additional genetic aberrations (CDKN2A or CDKN2B, PAX5, or both).

ABL1 mutations were present in six patients who had increased minimal residual disease during induction therapy. All these mutations were cleared by blinatumomab.

There were six relapses, of which three were hematologic. One occurred in a patient with a major protocol violation (a delay of more than 2 months in receiving blinatumomab), one occurred after 12 months in the patient who discontinued the trial after receiving dasatinib for 12 days, and one occurred in a patient after the second cycle of blinatumomab.

A total of 21 adverse events of grade 3 or higher were noted. They included cytomegalovirus reactivation or infection in six patients; neutropenia in four patients; persistent fever in two patients; and pleural effusion, pulmonary hypertension, and a neurologic disorder in one patient each.

Of the 24 patients who received a stem-cell allograft, two died, but only one death was related to transplant (4%).

The very low nonrelapse mortality among patients who underwent transplant during remission is “remarkable,” Dr. Hoelzer wrote. It suggests that toxicity from induction chemotherapy puts the patient at risk for toxic effects and death from subsequent stem-cell transplant – “a consequence that is avoided with targeted therapy.”
 

Unanswered questions

“Will the excellent outcomes be preserved with longer follow-up? The answer is probably yes, given that the majority of relapses in ALL occur within the first 1.5 to 2.0 years after the initiation of treatment,” Dr. Hoelzer wrote.

He said other outstanding questions include whether long-term outcomes will differ between patients who undergo transplant and those who do not; whether ABL1 mutations emerge; whether minimal residual disease recurs with longer follow-up; and whether this treatment approach can be used for patients with other subtypes of ALL, such as Ph-negative, B-lineage ALL, or even T-cell ALL.

“If these promising trial results hold, chemotherapy-free induction without the immediate and long-term toxic effects of intensive chemotherapy regimens could also be used in adolescents and, finally, in children. These questions will need to be addressed with longer follow-up and large, prospective trials,” Dr. Hoelzer concluded.

The study was supported by grants from the Italian Association for Cancer Research and Sapienza University of Rome.

A version of this article originally appeared on Medscape.com

Key clinical point: Several long noncoding RNAs (lncRNAs) were strongly associated with disease pathogenesis and prognosis in myelodysplastic syndrome (MDS) patients.

Major finding: Based on genome-wide profiling, lncRNA gene networks with expression of H19, WT1-AS, TCL6, and LEF1-AS1 were associated with higher-risk MDS; of these, H19 also showed promise as a therapeutic target because of its strong predictive value for lower complete remission rate of induction therapy in AML in the presence of H19 overexpression. 

Study details: The data come from a study of genetic profiling including 54 patients with MDS, 14 patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), and 9 healthy donors.

Disclosures: The study was supported by the Project for Conceptual Development of Research Organization from the Ministry of Health of the Czech Republic. The researchers had no financial conflicts to disclose.

Citation: Szikszai K et al. Cancers. 2020 Sept 23. doi: 10.3390/cancers12102726.

Key clinical point: Several long noncoding RNAs (lncRNAs) were strongly associated with disease pathogenesis and prognosis in myelodysplastic syndrome (MDS) patients.

Major finding: Based on genome-wide profiling, lncRNA gene networks with expression of H19, WT1-AS, TCL6, and LEF1-AS1 were associated with higher-risk MDS; of these, H19 also showed promise as a therapeutic target because of its strong predictive value for lower complete remission rate of induction therapy in AML in the presence of H19 overexpression. 

Study details: The data come from a study of genetic profiling including 54 patients with MDS, 14 patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), and 9 healthy donors.

Disclosures: The study was supported by the Project for Conceptual Development of Research Organization from the Ministry of Health of the Czech Republic. The researchers had no financial conflicts to disclose.

Citation: Szikszai K et al. Cancers. 2020 Sept 23. doi: 10.3390/cancers12102726.

Key clinical point: Several long noncoding RNAs (lncRNAs) were strongly associated with disease pathogenesis and prognosis in myelodysplastic syndrome (MDS) patients.

Major finding: Based on genome-wide profiling, lncRNA gene networks with expression of H19, WT1-AS, TCL6, and LEF1-AS1 were associated with higher-risk MDS; of these, H19 also showed promise as a therapeutic target because of its strong predictive value for lower complete remission rate of induction therapy in AML in the presence of H19 overexpression. 

Study details: The data come from a study of genetic profiling including 54 patients with MDS, 14 patients with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), and 9 healthy donors.

Disclosures: The study was supported by the Project for Conceptual Development of Research Organization from the Ministry of Health of the Czech Republic. The researchers had no financial conflicts to disclose.

Citation: Szikszai K et al. Cancers. 2020 Sept 23. doi: 10.3390/cancers12102726.

Key clinical point: Ferroptosis, a distinct form of regulated cell death process involving iron-dependent lipid peroxidation, may impact the action of chemotherapy drug decitabine.

Major finding: The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in MDS cells upon treatment with decitabine, which could be reversed by ferrostatin-1.

Study details: The data come from a review of cell viability assays, reactive oxygen species assays, gluthiathone assays, and

Disclosures: The study was supported in part by the National Natural Science Foundation of China, Key Technology Research and Development Program of Tianjin, Application Bases and Advanced Technology Research Program of Tianjin, and Key National Natural Science Foundation of Tianjin. The researchers had no financial conflicts to disclose.

Citation: Lv Q et al. Front. Oncol. 2020 Sept 2. doi: 10.3389/fonc.2020.01656.

Key clinical point: Ferroptosis, a distinct form of regulated cell death process involving iron-dependent lipid peroxidation, may impact the action of chemotherapy drug decitabine.

Major finding: The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in MDS cells upon treatment with decitabine, which could be reversed by ferrostatin-1.

Study details: The data come from a review of cell viability assays, reactive oxygen species assays, gluthiathone assays, and

Disclosures: The study was supported in part by the National Natural Science Foundation of China, Key Technology Research and Development Program of Tianjin, Application Bases and Advanced Technology Research Program of Tianjin, and Key National Natural Science Foundation of Tianjin. The researchers had no financial conflicts to disclose.

Citation: Lv Q et al. Front. Oncol. 2020 Sept 2. doi: 10.3389/fonc.2020.01656.

Key clinical point: Ferroptosis, a distinct form of regulated cell death process involving iron-dependent lipid peroxidation, may impact the action of chemotherapy drug decitabine.

Major finding: The level of GSH and the activity of GPX4 decreased, whereas the ROS level increased in MDS cells upon treatment with decitabine, which could be reversed by ferrostatin-1.

Study details: The data come from a review of cell viability assays, reactive oxygen species assays, gluthiathone assays, and

Disclosures: The study was supported in part by the National Natural Science Foundation of China, Key Technology Research and Development Program of Tianjin, Application Bases and Advanced Technology Research Program of Tianjin, and Key National Natural Science Foundation of Tianjin. The researchers had no financial conflicts to disclose.

Citation: Lv Q et al. Front. Oncol. 2020 Sept 2. doi: 10.3389/fonc.2020.01656.

Key clinical point: In a population of MDS patients with COVID-19 symptoms who underwent laboratory testing, 20.6% had confirmed cases.

Major finding: At the time of this analysis, 33 of 63 COVID-19 positive MDS patients were alive, suggesting a higher lethality rate in this population compared to the population at large.

Study details: The data come from a review of 5,326 adults with myelodysplastic syndromes who were symptomatic for COVID-19 between February 24 and April 28, 2020; 305 MDS patients underwent laboratory testing to confirm the infection.

Disclosures: The study was received no outside funding. The researchers had no financial conflicts to disclose.

Citation: Mossuto S et al. HemaSphere. 2020 Oct. doi: 10.1097/HS9.0000000000000483.

Key clinical point: In a population of MDS patients with COVID-19 symptoms who underwent laboratory testing, 20.6% had confirmed cases.

Major finding: At the time of this analysis, 33 of 63 COVID-19 positive MDS patients were alive, suggesting a higher lethality rate in this population compared to the population at large.

Study details: The data come from a review of 5,326 adults with myelodysplastic syndromes who were symptomatic for COVID-19 between February 24 and April 28, 2020; 305 MDS patients underwent laboratory testing to confirm the infection.

Disclosures: The study was received no outside funding. The researchers had no financial conflicts to disclose.

Citation: Mossuto S et al. HemaSphere. 2020 Oct. doi: 10.1097/HS9.0000000000000483.

Key clinical point: In a population of MDS patients with COVID-19 symptoms who underwent laboratory testing, 20.6% had confirmed cases.

Major finding: At the time of this analysis, 33 of 63 COVID-19 positive MDS patients were alive, suggesting a higher lethality rate in this population compared to the population at large.

Study details: The data come from a review of 5,326 adults with myelodysplastic syndromes who were symptomatic for COVID-19 between February 24 and April 28, 2020; 305 MDS patients underwent laboratory testing to confirm the infection.

Disclosures: The study was received no outside funding. The researchers had no financial conflicts to disclose.

Citation: Mossuto S et al. HemaSphere. 2020 Oct. doi: 10.1097/HS9.0000000000000483.