Neil Osterweil

COPENHAGEN – A year after stopping tyrosine kinase inhibitor therapy, more than half of patients with chronic myeloid leukemia (CML) in a large clinical trial remained in deep molecular remission.

Among 750 patients with CML in remission for at least 1 year before study entry, 62% retained a treatment response 6 months after stopping a tyrosine kinase inhibitor (TKI) such as imatinib (Gleevec) and 56% retained responses 1 year after being off their drugs, reported Dr. Johan Richter of Lund (Sweden) University at the annual congress of the European Hematology Association.

RTEmagicC_7a9b2b7b36508af010_Richter_Johan_SWEDEN.jpg.jpg

“About 6 years of therapy [with imatinib] would be optimal for therapy prior to a stop attempt,” he said at a briefing prior to the presentation of data at the congress.

Although in clinical practice patients with CML may remain on a TKI indefinitely, results from small clinical trials have suggested that in 40%-60% of patients with deep molecular responses (MR4.0 or better), TKIs can be safely stopped, Dr. Richter noted.

To get a better handle on when it might be safe to stop a TKI and under what conditions, EURO-SKI investigators enrolled 868 adults with CML in chronic phase from 11 countries, 750 of whom had complete data for the analysis.

In all, 94% of patients had received imatinib in the first line, 2% received dasatinib (Sprycel), and 4% had received nilotinib (Tasigna). Of this group, 115 had switched to a second-line agent due to intolerance of the first-line drug.

The median time from diagnosis was 7.7 years. The median duration of therapy was 7.6 years, and the median duration of MR4 before stopping was 4.7 years.

As noted, among 750 patients assessable for molecular relapse–free survival, 62% remained in remission at 6 months after stopping the TKI, as did 56% at 12 months, 52% at 24 months, and 49% at 36 months.

For patients who resumed therapy, the median time to restart was 4.1 months.

To see whether they could identify any factors prognostic for relapse after stopping a TKI, the investigators used data on 448 patients in the study who were treated with imatinib.

In univariate analysis there was no significant association between molecular relapse–free survival at 6 months and either age, gender, depth of molecular response, or any standard risk scores.

The only significant predictors of molecular remission status at 6 months were duration of imatinib therapy and duration of molecular response before stopping.

The odds ratio for treatment duration was 1.16, indicating that each additional year of imatinib treatment is associated with a 16% increase in the likelihood that a patient would remain in deep molecular remission 6 months after stopping.

The investigators used the minimal P value approach to determine the cutoff of approximately 6 years, based on a molecular relapse–free survival at 6 months of 65.5% for patients who remained on imatinib for more than 5.8 years, compared with 42.6% for those who were on it for 5.8 years or less.

Although the study is ongoing, to date more than 80% of patients who had a loss of deep molecular remission after stopping their TKI regained the remission after resuming therapy, Dr. Richter said.

Dr. Richter said in an interview that longer follow-up will be needed to confirm their findings, and that patients who were sensitive to TKIs prior to stopping therapy remained sensitive when restarting, suggesting that treatment interruption does not increase the likelihood of drug resistance.

Coprincipal investigator Dr. Francois-Xavier Mahon of Bordeaux University in France, noted that in the STIM (Stop Imatinib)–1 and –2 trials, the estimated annual savings to the French health care system were 20 million euros ($22.6 million).

COPENHAGEN – A year after stopping tyrosine kinase inhibitor therapy, more than half of patients with chronic myeloid leukemia (CML) in a large clinical trial remained in deep molecular remission.

Among 750 patients with CML in remission for at least 1 year before study entry, 62% retained a treatment response 6 months after stopping a tyrosine kinase inhibitor (TKI) such as imatinib (Gleevec) and 56% retained responses 1 year after being off their drugs, reported Dr. Johan Richter of Lund (Sweden) University at the annual congress of the European Hematology Association.

RTEmagicC_7a9b2b7b36508af010_Richter_Johan_SWEDEN.jpg.jpg

“About 6 years of therapy [with imatinib] would be optimal for therapy prior to a stop attempt,” he said at a briefing prior to the presentation of data at the congress.

Although in clinical practice patients with CML may remain on a TKI indefinitely, results from small clinical trials have suggested that in 40%-60% of patients with deep molecular responses (MR4.0 or better), TKIs can be safely stopped, Dr. Richter noted.

To get a better handle on when it might be safe to stop a TKI and under what conditions, EURO-SKI investigators enrolled 868 adults with CML in chronic phase from 11 countries, 750 of whom had complete data for the analysis.

In all, 94% of patients had received imatinib in the first line, 2% received dasatinib (Sprycel), and 4% had received nilotinib (Tasigna). Of this group, 115 had switched to a second-line agent due to intolerance of the first-line drug.

The median time from diagnosis was 7.7 years. The median duration of therapy was 7.6 years, and the median duration of MR4 before stopping was 4.7 years.

As noted, among 750 patients assessable for molecular relapse–free survival, 62% remained in remission at 6 months after stopping the TKI, as did 56% at 12 months, 52% at 24 months, and 49% at 36 months.

For patients who resumed therapy, the median time to restart was 4.1 months.

To see whether they could identify any factors prognostic for relapse after stopping a TKI, the investigators used data on 448 patients in the study who were treated with imatinib.

In univariate analysis there was no significant association between molecular relapse–free survival at 6 months and either age, gender, depth of molecular response, or any standard risk scores.

The only significant predictors of molecular remission status at 6 months were duration of imatinib therapy and duration of molecular response before stopping.

The odds ratio for treatment duration was 1.16, indicating that each additional year of imatinib treatment is associated with a 16% increase in the likelihood that a patient would remain in deep molecular remission 6 months after stopping.

The investigators used the minimal P value approach to determine the cutoff of approximately 6 years, based on a molecular relapse–free survival at 6 months of 65.5% for patients who remained on imatinib for more than 5.8 years, compared with 42.6% for those who were on it for 5.8 years or less.

Although the study is ongoing, to date more than 80% of patients who had a loss of deep molecular remission after stopping their TKI regained the remission after resuming therapy, Dr. Richter said.

Dr. Richter said in an interview that longer follow-up will be needed to confirm their findings, and that patients who were sensitive to TKIs prior to stopping therapy remained sensitive when restarting, suggesting that treatment interruption does not increase the likelihood of drug resistance.

Coprincipal investigator Dr. Francois-Xavier Mahon of Bordeaux University in France, noted that in the STIM (Stop Imatinib)–1 and –2 trials, the estimated annual savings to the French health care system were 20 million euros ($22.6 million).

COPENHAGEN – A year after stopping tyrosine kinase inhibitor therapy, more than half of patients with chronic myeloid leukemia (CML) in a large clinical trial remained in deep molecular remission.

Among 750 patients with CML in remission for at least 1 year before study entry, 62% retained a treatment response 6 months after stopping a tyrosine kinase inhibitor (TKI) such as imatinib (Gleevec) and 56% retained responses 1 year after being off their drugs, reported Dr. Johan Richter of Lund (Sweden) University at the annual congress of the European Hematology Association.

RTEmagicC_7a9b2b7b36508af010_Richter_Johan_SWEDEN.jpg.jpg

“About 6 years of therapy [with imatinib] would be optimal for therapy prior to a stop attempt,” he said at a briefing prior to the presentation of data at the congress.

Although in clinical practice patients with CML may remain on a TKI indefinitely, results from small clinical trials have suggested that in 40%-60% of patients with deep molecular responses (MR4.0 or better), TKIs can be safely stopped, Dr. Richter noted.

To get a better handle on when it might be safe to stop a TKI and under what conditions, EURO-SKI investigators enrolled 868 adults with CML in chronic phase from 11 countries, 750 of whom had complete data for the analysis.

In all, 94% of patients had received imatinib in the first line, 2% received dasatinib (Sprycel), and 4% had received nilotinib (Tasigna). Of this group, 115 had switched to a second-line agent due to intolerance of the first-line drug.

The median time from diagnosis was 7.7 years. The median duration of therapy was 7.6 years, and the median duration of MR4 before stopping was 4.7 years.

As noted, among 750 patients assessable for molecular relapse–free survival, 62% remained in remission at 6 months after stopping the TKI, as did 56% at 12 months, 52% at 24 months, and 49% at 36 months.

For patients who resumed therapy, the median time to restart was 4.1 months.

To see whether they could identify any factors prognostic for relapse after stopping a TKI, the investigators used data on 448 patients in the study who were treated with imatinib.

In univariate analysis there was no significant association between molecular relapse–free survival at 6 months and either age, gender, depth of molecular response, or any standard risk scores.

The only significant predictors of molecular remission status at 6 months were duration of imatinib therapy and duration of molecular response before stopping.

The odds ratio for treatment duration was 1.16, indicating that each additional year of imatinib treatment is associated with a 16% increase in the likelihood that a patient would remain in deep molecular remission 6 months after stopping.

The investigators used the minimal P value approach to determine the cutoff of approximately 6 years, based on a molecular relapse–free survival at 6 months of 65.5% for patients who remained on imatinib for more than 5.8 years, compared with 42.6% for those who were on it for 5.8 years or less.

Although the study is ongoing, to date more than 80% of patients who had a loss of deep molecular remission after stopping their TKI regained the remission after resuming therapy, Dr. Richter said.

Dr. Richter said in an interview that longer follow-up will be needed to confirm their findings, and that patients who were sensitive to TKIs prior to stopping therapy remained sensitive when restarting, suggesting that treatment interruption does not increase the likelihood of drug resistance.

Coprincipal investigator Dr. Francois-Xavier Mahon of Bordeaux University in France, noted that in the STIM (Stop Imatinib)–1 and –2 trials, the estimated annual savings to the French health care system were 20 million euros ($22.6 million).

COPENHAGEN – In a classic case of clinical sibling rivalry, results of the POLLUX trial support the benefits of adding daratumumab to lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma, echoing results reported a few days earlier by investigators in the twin (and archly named) CASTOR trial

Among 569 patients with relapsed/refractory multiple myeloma, the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex) to lenalidomide (Revlimid) and dexamethasone was associated with a 63% reduction in the risk of disease progress or death, compared with len-dex alone, reported Dr. Meletios A Dimopoulos of the National and Kapodistrian University of Athens.

RTEmagicC_dbae00e799384d56f6_Dimopoulos_Meletios_A_GREECE.jpg.jpg

With daratumumab and len-dex, “there is the highest-ever response rate seen in relapsed or refractory myeloma; 93% of the patients achieved at least a partial response, and more importantly, 43% of the patients achieved a complete response,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

“The addition of daratumumab to lenalidomide and dexamethasone induces deep and durable responses. Data indicate that we can achieve minimal residual disease negativity status in a significant number of patients,” he added.

The trial was halted on May 20, 2016, after a preplanned interim analysis showed a significant improvement in the primary endpoint of a progression-free survival, compared with len-dex alone.

Dizygotic twins

Like their mythologic namesakes, who were twin sons from different fathers, the CASTOR and POLLUX trials differed somewhat in the patient populations treated and in trial design. The CASTOR trial is looking at the addition of daratumumab to bortezomib (Velcade) and dexamethasone, and excludes patients resistant to bortezomib. The POLLUX trial includes bortezomib-resistant patients, but excludes lenalidomide-resistant patients.

In addition, in CASTOR, patients were treated with the assigned regimen for a specified number of courses, followed by daratumumab maintenance, whereas patients in both arms in POLLUX continued on their assigned therapy until disease progression or unacceptable toxicity occurred.

POLLUX was a multicenter, randomized, open-label phase III trial in patients with relapsed/refractory multiple myeloma following one or more prior lines of therapy. They were randomized on a 1:1 basis to either len-dex (283 patients) or len-dex plus intravenous daratumumab at a dose of 16 mg/kg once a week during treatment cycles 1 and 2, every 2 weeks during cycles 3-6, and once only on day 1 of subsequent cycles.

After a median follow-up of 13.5 months, the median progression-free survival for patients treated with len-dex alone was 18.4 months, but the median was not yet reached among patients treated with daratumumab. The difference translated into a hazard ratio for progression-free survival with daratumumab of 0.37 (P less than .0001).

In addition, the antibody was associated with a significantly better overall response rate (93% for daratumumab vs. 76% for len-dex only; P less than .0001), as well as better rates of complete responses (43% vs. 19%, respectively; P less than .0001), and very good partial responses or better (76% vs. 44%, P less than .0001).

The combination was generally well tolerated, with adverse events consistent with the known safety profile of len-dex. Infusion reactions with daratumumab were generally mild, and tended to occur during the first infusion, Dr. Dimopoulos said.

RTEmagicC_dbae00e799384d56f6_Hagenbeek_Anton_NETHERLANDS2.jpg.jpg

Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam (the Netherlands), who moderated the briefing, commented that the progression-free survival curves with daratumumab appeared to plateau, and asked whether any patients in the trial could be considered to have been “cured.”

Dr. Dimopoulos replied that “although we believe that in the relapsed setting of myeloma, it is unlikely to achieve the cure rate, we are optimistic that there will be a sizable number of patients that will remain without progression for many months. Already from single-agent daratumumab where this patient population is far more heavily pretreated, there are patients who are without progression for several years.”

Dr. Dimopoulos has previously disclosed honoraria from Janssen, maker of daratumumab. Dr. Hagenbeek disclosed serving on an advisory board for Takeda, maker of bortezomib.

COPENHAGEN – In a classic case of clinical sibling rivalry, results of the POLLUX trial support the benefits of adding daratumumab to lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma, echoing results reported a few days earlier by investigators in the twin (and archly named) CASTOR trial

Among 569 patients with relapsed/refractory multiple myeloma, the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex) to lenalidomide (Revlimid) and dexamethasone was associated with a 63% reduction in the risk of disease progress or death, compared with len-dex alone, reported Dr. Meletios A Dimopoulos of the National and Kapodistrian University of Athens.

RTEmagicC_dbae00e799384d56f6_Dimopoulos_Meletios_A_GREECE.jpg.jpg

With daratumumab and len-dex, “there is the highest-ever response rate seen in relapsed or refractory myeloma; 93% of the patients achieved at least a partial response, and more importantly, 43% of the patients achieved a complete response,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

“The addition of daratumumab to lenalidomide and dexamethasone induces deep and durable responses. Data indicate that we can achieve minimal residual disease negativity status in a significant number of patients,” he added.

The trial was halted on May 20, 2016, after a preplanned interim analysis showed a significant improvement in the primary endpoint of a progression-free survival, compared with len-dex alone.

Dizygotic twins

Like their mythologic namesakes, who were twin sons from different fathers, the CASTOR and POLLUX trials differed somewhat in the patient populations treated and in trial design. The CASTOR trial is looking at the addition of daratumumab to bortezomib (Velcade) and dexamethasone, and excludes patients resistant to bortezomib. The POLLUX trial includes bortezomib-resistant patients, but excludes lenalidomide-resistant patients.

In addition, in CASTOR, patients were treated with the assigned regimen for a specified number of courses, followed by daratumumab maintenance, whereas patients in both arms in POLLUX continued on their assigned therapy until disease progression or unacceptable toxicity occurred.

POLLUX was a multicenter, randomized, open-label phase III trial in patients with relapsed/refractory multiple myeloma following one or more prior lines of therapy. They were randomized on a 1:1 basis to either len-dex (283 patients) or len-dex plus intravenous daratumumab at a dose of 16 mg/kg once a week during treatment cycles 1 and 2, every 2 weeks during cycles 3-6, and once only on day 1 of subsequent cycles.

After a median follow-up of 13.5 months, the median progression-free survival for patients treated with len-dex alone was 18.4 months, but the median was not yet reached among patients treated with daratumumab. The difference translated into a hazard ratio for progression-free survival with daratumumab of 0.37 (P less than .0001).

In addition, the antibody was associated with a significantly better overall response rate (93% for daratumumab vs. 76% for len-dex only; P less than .0001), as well as better rates of complete responses (43% vs. 19%, respectively; P less than .0001), and very good partial responses or better (76% vs. 44%, P less than .0001).

The combination was generally well tolerated, with adverse events consistent with the known safety profile of len-dex. Infusion reactions with daratumumab were generally mild, and tended to occur during the first infusion, Dr. Dimopoulos said.

RTEmagicC_dbae00e799384d56f6_Hagenbeek_Anton_NETHERLANDS2.jpg.jpg

Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam (the Netherlands), who moderated the briefing, commented that the progression-free survival curves with daratumumab appeared to plateau, and asked whether any patients in the trial could be considered to have been “cured.”

Dr. Dimopoulos replied that “although we believe that in the relapsed setting of myeloma, it is unlikely to achieve the cure rate, we are optimistic that there will be a sizable number of patients that will remain without progression for many months. Already from single-agent daratumumab where this patient population is far more heavily pretreated, there are patients who are without progression for several years.”

Dr. Dimopoulos has previously disclosed honoraria from Janssen, maker of daratumumab. Dr. Hagenbeek disclosed serving on an advisory board for Takeda, maker of bortezomib.

COPENHAGEN – In a classic case of clinical sibling rivalry, results of the POLLUX trial support the benefits of adding daratumumab to lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma, echoing results reported a few days earlier by investigators in the twin (and archly named) CASTOR trial

Among 569 patients with relapsed/refractory multiple myeloma, the addition of the anti-CD38 monoclonal antibody daratumumab (Darzalex) to lenalidomide (Revlimid) and dexamethasone was associated with a 63% reduction in the risk of disease progress or death, compared with len-dex alone, reported Dr. Meletios A Dimopoulos of the National and Kapodistrian University of Athens.

RTEmagicC_dbae00e799384d56f6_Dimopoulos_Meletios_A_GREECE.jpg.jpg

With daratumumab and len-dex, “there is the highest-ever response rate seen in relapsed or refractory myeloma; 93% of the patients achieved at least a partial response, and more importantly, 43% of the patients achieved a complete response,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

“The addition of daratumumab to lenalidomide and dexamethasone induces deep and durable responses. Data indicate that we can achieve minimal residual disease negativity status in a significant number of patients,” he added.

The trial was halted on May 20, 2016, after a preplanned interim analysis showed a significant improvement in the primary endpoint of a progression-free survival, compared with len-dex alone.

Dizygotic twins

Like their mythologic namesakes, who were twin sons from different fathers, the CASTOR and POLLUX trials differed somewhat in the patient populations treated and in trial design. The CASTOR trial is looking at the addition of daratumumab to bortezomib (Velcade) and dexamethasone, and excludes patients resistant to bortezomib. The POLLUX trial includes bortezomib-resistant patients, but excludes lenalidomide-resistant patients.

In addition, in CASTOR, patients were treated with the assigned regimen for a specified number of courses, followed by daratumumab maintenance, whereas patients in both arms in POLLUX continued on their assigned therapy until disease progression or unacceptable toxicity occurred.

POLLUX was a multicenter, randomized, open-label phase III trial in patients with relapsed/refractory multiple myeloma following one or more prior lines of therapy. They were randomized on a 1:1 basis to either len-dex (283 patients) or len-dex plus intravenous daratumumab at a dose of 16 mg/kg once a week during treatment cycles 1 and 2, every 2 weeks during cycles 3-6, and once only on day 1 of subsequent cycles.

After a median follow-up of 13.5 months, the median progression-free survival for patients treated with len-dex alone was 18.4 months, but the median was not yet reached among patients treated with daratumumab. The difference translated into a hazard ratio for progression-free survival with daratumumab of 0.37 (P less than .0001).

In addition, the antibody was associated with a significantly better overall response rate (93% for daratumumab vs. 76% for len-dex only; P less than .0001), as well as better rates of complete responses (43% vs. 19%, respectively; P less than .0001), and very good partial responses or better (76% vs. 44%, P less than .0001).

The combination was generally well tolerated, with adverse events consistent with the known safety profile of len-dex. Infusion reactions with daratumumab were generally mild, and tended to occur during the first infusion, Dr. Dimopoulos said.

RTEmagicC_dbae00e799384d56f6_Hagenbeek_Anton_NETHERLANDS2.jpg.jpg

Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam (the Netherlands), who moderated the briefing, commented that the progression-free survival curves with daratumumab appeared to plateau, and asked whether any patients in the trial could be considered to have been “cured.”

Dr. Dimopoulos replied that “although we believe that in the relapsed setting of myeloma, it is unlikely to achieve the cure rate, we are optimistic that there will be a sizable number of patients that will remain without progression for many months. Already from single-agent daratumumab where this patient population is far more heavily pretreated, there are patients who are without progression for several years.”

Dr. Dimopoulos has previously disclosed honoraria from Janssen, maker of daratumumab. Dr. Hagenbeek disclosed serving on an advisory board for Takeda, maker of bortezomib.

Copenhagen – The monoclonal antibody blinatumomab nearly doubled overall survival compared with standard chemotherapy among patients with relapsed or refractory B-cell precursor leukemia negative for the Philadelphia chromosome, investigators reported.

Among 405 patients enrolled in the TOWER study, a multicenter, open-label phase III trial, median overall survival for patients treated with blinatumomab (Blincyto) was 7.7 months, compared with 4.0 months for patients treated with one of four standard chemotherapy regimens (P = .012) reported Dr. Max S. Topp of Universitätsklinikum in Würzburg, Germany.

RTEmagicC_033e283a898289d75d_Topp_Max_S_GERMANY2.jpg.jpg

“Blinatumomab is the first immunotherapy agent to demonstrate an overall survival benefit when compared to chemotherapy in patients relapsing with adult acute lymphoblastic leukemia. It increases almost twofold the overall survival when compared to standard care. This was consistent in all subgroups that we were looking at, regardless of age, prior salvage therapy, or patients relapsing after an allo-transplantation,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

The trial was halted early, after a preplanned interim analysis showed a clear survival benefit with blinatumomab.

Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. As previously reported, it has induced high complete remission rates in patients with relapsed or refractory acute lymphoblastic leukemia (ALL).

In May 2015, the Food and Drug Administration granted blinatumomab accelerated approval for the treatment of adult patients with relapsed/refractory Philadelphia chromosome–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

In the TOWER trial, patients with relapsed/refractory BCP-ALL were randomly assigned on a 2:1 basis to receive either blinatumomab (271 patients) or standard chemotherapy (134), consisting of the investigator’s choice of one of four defined regimens (based on either anthracyclines, histone deacetylase inhibitors, high-dose methotrexate, or clofarabine).

The patients were further stratified by age, prior salvage therapy, and prior allogeneic stem cell transplant (alloSCT).

Patients assigned to receive blinatumomab received it in 6-week cycles consisting of continuous infusions of 9 mcg/day in week 1 of cycle 1, then 28 mcg/day for weeks 3-4, followed by 2 weeks off. Patients were pretreated with dexamethasone for prophylaxis against the cytokine release syndrome.

Patients whose disease was in remission following two induction cycles could be continued on therapy until relapse.

As noted, the trial was halted early, after 248 patients had died; the primary analysis had been planned to occur after 330 patients had died.

In addition to the superior survival rates, blinatumomab was associated with a higher rate of complete responses (39% vs. 19%, P less than .001) and combined complete responses, complete hematologic responses, and complete responses with incomplete recovery of counts (46% vs. 28%, P = .001).

In all, 19% of patients assigned to blinatumomab and 17% assigned to chemotherapy died on study. Grade 3 or greater adverse events included neutropenia (38% of patients and 58%, respectively), infections (34% and 52%), neurologic events (9% and 8%), and the cytokine release syndrome (5% vs. 0%).

Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who moderated the briefing, asked Dr. Topp whether there were plans to use blinatumomab earlier in the course of disease.

Dr. Topp agreed that it might be a valuable addition to upfront therapy, noting that blinatumomab has been shown in a small percentage of patients who are positive for minimal residual disease to convert to being negative for minimal residual disease, and that this conversion was associated with improved overall survival.

Copenhagen – The monoclonal antibody blinatumomab nearly doubled overall survival compared with standard chemotherapy among patients with relapsed or refractory B-cell precursor leukemia negative for the Philadelphia chromosome, investigators reported.

Among 405 patients enrolled in the TOWER study, a multicenter, open-label phase III trial, median overall survival for patients treated with blinatumomab (Blincyto) was 7.7 months, compared with 4.0 months for patients treated with one of four standard chemotherapy regimens (P = .012) reported Dr. Max S. Topp of Universitätsklinikum in Würzburg, Germany.

RTEmagicC_033e283a898289d75d_Topp_Max_S_GERMANY2.jpg.jpg

“Blinatumomab is the first immunotherapy agent to demonstrate an overall survival benefit when compared to chemotherapy in patients relapsing with adult acute lymphoblastic leukemia. It increases almost twofold the overall survival when compared to standard care. This was consistent in all subgroups that we were looking at, regardless of age, prior salvage therapy, or patients relapsing after an allo-transplantation,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

The trial was halted early, after a preplanned interim analysis showed a clear survival benefit with blinatumomab.

Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. As previously reported, it has induced high complete remission rates in patients with relapsed or refractory acute lymphoblastic leukemia (ALL).

In May 2015, the Food and Drug Administration granted blinatumomab accelerated approval for the treatment of adult patients with relapsed/refractory Philadelphia chromosome–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

In the TOWER trial, patients with relapsed/refractory BCP-ALL were randomly assigned on a 2:1 basis to receive either blinatumomab (271 patients) or standard chemotherapy (134), consisting of the investigator’s choice of one of four defined regimens (based on either anthracyclines, histone deacetylase inhibitors, high-dose methotrexate, or clofarabine).

The patients were further stratified by age, prior salvage therapy, and prior allogeneic stem cell transplant (alloSCT).

Patients assigned to receive blinatumomab received it in 6-week cycles consisting of continuous infusions of 9 mcg/day in week 1 of cycle 1, then 28 mcg/day for weeks 3-4, followed by 2 weeks off. Patients were pretreated with dexamethasone for prophylaxis against the cytokine release syndrome.

Patients whose disease was in remission following two induction cycles could be continued on therapy until relapse.

As noted, the trial was halted early, after 248 patients had died; the primary analysis had been planned to occur after 330 patients had died.

In addition to the superior survival rates, blinatumomab was associated with a higher rate of complete responses (39% vs. 19%, P less than .001) and combined complete responses, complete hematologic responses, and complete responses with incomplete recovery of counts (46% vs. 28%, P = .001).

In all, 19% of patients assigned to blinatumomab and 17% assigned to chemotherapy died on study. Grade 3 or greater adverse events included neutropenia (38% of patients and 58%, respectively), infections (34% and 52%), neurologic events (9% and 8%), and the cytokine release syndrome (5% vs. 0%).

Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who moderated the briefing, asked Dr. Topp whether there were plans to use blinatumomab earlier in the course of disease.

Dr. Topp agreed that it might be a valuable addition to upfront therapy, noting that blinatumomab has been shown in a small percentage of patients who are positive for minimal residual disease to convert to being negative for minimal residual disease, and that this conversion was associated with improved overall survival.

Copenhagen – The monoclonal antibody blinatumomab nearly doubled overall survival compared with standard chemotherapy among patients with relapsed or refractory B-cell precursor leukemia negative for the Philadelphia chromosome, investigators reported.

Among 405 patients enrolled in the TOWER study, a multicenter, open-label phase III trial, median overall survival for patients treated with blinatumomab (Blincyto) was 7.7 months, compared with 4.0 months for patients treated with one of four standard chemotherapy regimens (P = .012) reported Dr. Max S. Topp of Universitätsklinikum in Würzburg, Germany.

RTEmagicC_033e283a898289d75d_Topp_Max_S_GERMANY2.jpg.jpg

“Blinatumomab is the first immunotherapy agent to demonstrate an overall survival benefit when compared to chemotherapy in patients relapsing with adult acute lymphoblastic leukemia. It increases almost twofold the overall survival when compared to standard care. This was consistent in all subgroups that we were looking at, regardless of age, prior salvage therapy, or patients relapsing after an allo-transplantation,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

The trial was halted early, after a preplanned interim analysis showed a clear survival benefit with blinatumomab.

Blinatumomab is a bispecific T-cell engager (BiTE) antibody designed to direct cytotoxic T cells to cancer cells expressing the CD19 receptor. As previously reported, it has induced high complete remission rates in patients with relapsed or refractory acute lymphoblastic leukemia (ALL).

In May 2015, the Food and Drug Administration granted blinatumomab accelerated approval for the treatment of adult patients with relapsed/refractory Philadelphia chromosome–negative B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

In the TOWER trial, patients with relapsed/refractory BCP-ALL were randomly assigned on a 2:1 basis to receive either blinatumomab (271 patients) or standard chemotherapy (134), consisting of the investigator’s choice of one of four defined regimens (based on either anthracyclines, histone deacetylase inhibitors, high-dose methotrexate, or clofarabine).

The patients were further stratified by age, prior salvage therapy, and prior allogeneic stem cell transplant (alloSCT).

Patients assigned to receive blinatumomab received it in 6-week cycles consisting of continuous infusions of 9 mcg/day in week 1 of cycle 1, then 28 mcg/day for weeks 3-4, followed by 2 weeks off. Patients were pretreated with dexamethasone for prophylaxis against the cytokine release syndrome.

Patients whose disease was in remission following two induction cycles could be continued on therapy until relapse.

As noted, the trial was halted early, after 248 patients had died; the primary analysis had been planned to occur after 330 patients had died.

In addition to the superior survival rates, blinatumomab was associated with a higher rate of complete responses (39% vs. 19%, P less than .001) and combined complete responses, complete hematologic responses, and complete responses with incomplete recovery of counts (46% vs. 28%, P = .001).

In all, 19% of patients assigned to blinatumomab and 17% assigned to chemotherapy died on study. Grade 3 or greater adverse events included neutropenia (38% of patients and 58%, respectively), infections (34% and 52%), neurologic events (9% and 8%), and the cytokine release syndrome (5% vs. 0%).

Dr. Anton Hagenbeek, professor of hematology at the University of Amsterdam, who moderated the briefing, asked Dr. Topp whether there were plans to use blinatumomab earlier in the course of disease.

Dr. Topp agreed that it might be a valuable addition to upfront therapy, noting that blinatumomab has been shown in a small percentage of patients who are positive for minimal residual disease to convert to being negative for minimal residual disease, and that this conversion was associated with improved overall survival.

Copenhagen – Among older adults with acute myeloid leukemia, the combination of a drug-antibody conjugate and hypomethylating therapy was associated with high complete remission rates.

In a phase I study of 53 patients (median age 75 years) with AML, the combination of vadastuximab talirine and a hypomethylating agent (HMA), either azacitidine or decitabine, was associated in 49 efficacy-evaluable patients with a 71% rate of composite complete remission (CR) and complete remission with incomplete recovery of counts (CRi), reported Dr. Amir Fathi from the Massachusetts General Hospital Cancer Center in Boston.

“This high remission rate in this traditionally high risk group and difficult to treat population is very compelling. Response rates were higher, and were achieved more quickly than would be expected from historical data associated with HMA therapy alone,” he said at a briefing at the annual congress of the European Hematology Association.

Many older patients with AML may not be able to withstand the rigors of cytotoxic chemotherapy, and these patients are often treated with hypomethylating agents or other low-intensity therapies, Dr. Fathi said.

Vadastuximab talirine is an antibody-drug conjugate designed to deliver a cytotoxic agent to myeloid leukemia cells, and in preclinical studies has been shown to enhance the cytotoxic effects of HMAs when given in combination.

Dr. Fathi reported preliminary data on 53 patients enrolled in a phase 1 study of the safety, tolerability, pharmacokinetics, and antileukemic activity of vadastuximab in combination with an HMA.

RTEmagicC_6a2ff6322f9166a4e0_Fathi_Amir_Boston.jpg.jpg

They enrolled adults with good performance status (Eastern Cooperative Oncology Group 0 or 1) who had CD33-positive AML and had declined intensive chemotherapy. They were given vadastuximab 10 mg/kg in an outpatient intravenous basis every 4 weeks on the fifth day of a 5-day HMA regimen,

Patients who were observed to have a clinical benefit could continue on treatment until relapse or unacceptable toxicity.

Of the 53 patients enrolled, 19 had adverse cytogenetic risk, and 30 had intermediate risk. The majority of patients (48) had not previously been treated for AML, and 5 had received prior low-intensity therapy for the myelodysplastic syndrome.

A total of 49 patients had sufficient data for the efficacy evaluation, and among these patients the composite CR/CRi rate was 71%; the rates of CR/CRi were similar whether the partner HMA was azacitadine or decitabine.

The overall response rate was 76%, with responses seem among higher-risk patients, including remissions in 16 of 22 patients with underlying myelodysplasia, and in 15 of 18 patients with adverse cytogenetics.

In addition, 8 of 19 patients with a CR, and 5 of 15 with a CRi met the definition for minimal residual disease.

Dr. Fathi reported early overall survival results, which he noted were still evolving. The estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months after a median follow-up of 12.58 months.

The median relapse free-survival was 7.7 months. As of last follow-up, 27 patients were alive and remained on study.

The 30-day mortality rate was 2%, and the 60-day rate was 8%.

The most common treatment-related adverse events of any grade occurring in 20% or more of patients were fatigue, thrombocytopenia, nausea, febrile neutropenia, constipation, and anemia

The most common grade 3 or greater treatment-emergent adverse events were febrile neutropenia, thrombocytopenia, neutropenia, anemia, and fatigue.

In an interview, Dr. Fathi said that he has been very encouraged by the results thus far.

“This is a traditionally high-risk patient population. Even with a conventional induction cytotoxic chemotherapy, rates of remission in this population are relatively lower, so if the remission rates pan out in a larger population, I would say it competes and possibly supersedes what you would expect in an older population,” Dr. Fathi said.

Asked whether it might be possible to boost outcomes further with additional therapies, he said that “I’m not sure if there is much more improvement over what we are already seeing; a rate of 70-something percent among older adults with AML is quite good.”

“I like this ‘Trojan-horse’ approach to treating AML,” commented Dr. Anton Hagenbeek, professor of hematology at the Academic Medical Center, University of Amsterdam, who moderated the briefing.

A randomized phase III trial of vadastuximab talirine and HMA therapy is currently enrolling patients.

The study was funded by Seattle Genetics. Dr. Fathi reported no relevant disclosures.

Copenhagen – Among older adults with acute myeloid leukemia, the combination of a drug-antibody conjugate and hypomethylating therapy was associated with high complete remission rates.

In a phase I study of 53 patients (median age 75 years) with AML, the combination of vadastuximab talirine and a hypomethylating agent (HMA), either azacitidine or decitabine, was associated in 49 efficacy-evaluable patients with a 71% rate of composite complete remission (CR) and complete remission with incomplete recovery of counts (CRi), reported Dr. Amir Fathi from the Massachusetts General Hospital Cancer Center in Boston.

“This high remission rate in this traditionally high risk group and difficult to treat population is very compelling. Response rates were higher, and were achieved more quickly than would be expected from historical data associated with HMA therapy alone,” he said at a briefing at the annual congress of the European Hematology Association.

Many older patients with AML may not be able to withstand the rigors of cytotoxic chemotherapy, and these patients are often treated with hypomethylating agents or other low-intensity therapies, Dr. Fathi said.

Vadastuximab talirine is an antibody-drug conjugate designed to deliver a cytotoxic agent to myeloid leukemia cells, and in preclinical studies has been shown to enhance the cytotoxic effects of HMAs when given in combination.

Dr. Fathi reported preliminary data on 53 patients enrolled in a phase 1 study of the safety, tolerability, pharmacokinetics, and antileukemic activity of vadastuximab in combination with an HMA.

RTEmagicC_6a2ff6322f9166a4e0_Fathi_Amir_Boston.jpg.jpg

They enrolled adults with good performance status (Eastern Cooperative Oncology Group 0 or 1) who had CD33-positive AML and had declined intensive chemotherapy. They were given vadastuximab 10 mg/kg in an outpatient intravenous basis every 4 weeks on the fifth day of a 5-day HMA regimen,

Patients who were observed to have a clinical benefit could continue on treatment until relapse or unacceptable toxicity.

Of the 53 patients enrolled, 19 had adverse cytogenetic risk, and 30 had intermediate risk. The majority of patients (48) had not previously been treated for AML, and 5 had received prior low-intensity therapy for the myelodysplastic syndrome.

A total of 49 patients had sufficient data for the efficacy evaluation, and among these patients the composite CR/CRi rate was 71%; the rates of CR/CRi were similar whether the partner HMA was azacitadine or decitabine.

The overall response rate was 76%, with responses seem among higher-risk patients, including remissions in 16 of 22 patients with underlying myelodysplasia, and in 15 of 18 patients with adverse cytogenetics.

In addition, 8 of 19 patients with a CR, and 5 of 15 with a CRi met the definition for minimal residual disease.

Dr. Fathi reported early overall survival results, which he noted were still evolving. The estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months after a median follow-up of 12.58 months.

The median relapse free-survival was 7.7 months. As of last follow-up, 27 patients were alive and remained on study.

The 30-day mortality rate was 2%, and the 60-day rate was 8%.

The most common treatment-related adverse events of any grade occurring in 20% or more of patients were fatigue, thrombocytopenia, nausea, febrile neutropenia, constipation, and anemia

The most common grade 3 or greater treatment-emergent adverse events were febrile neutropenia, thrombocytopenia, neutropenia, anemia, and fatigue.

In an interview, Dr. Fathi said that he has been very encouraged by the results thus far.

“This is a traditionally high-risk patient population. Even with a conventional induction cytotoxic chemotherapy, rates of remission in this population are relatively lower, so if the remission rates pan out in a larger population, I would say it competes and possibly supersedes what you would expect in an older population,” Dr. Fathi said.

Asked whether it might be possible to boost outcomes further with additional therapies, he said that “I’m not sure if there is much more improvement over what we are already seeing; a rate of 70-something percent among older adults with AML is quite good.”

“I like this ‘Trojan-horse’ approach to treating AML,” commented Dr. Anton Hagenbeek, professor of hematology at the Academic Medical Center, University of Amsterdam, who moderated the briefing.

A randomized phase III trial of vadastuximab talirine and HMA therapy is currently enrolling patients.

The study was funded by Seattle Genetics. Dr. Fathi reported no relevant disclosures.

Copenhagen – Among older adults with acute myeloid leukemia, the combination of a drug-antibody conjugate and hypomethylating therapy was associated with high complete remission rates.

In a phase I study of 53 patients (median age 75 years) with AML, the combination of vadastuximab talirine and a hypomethylating agent (HMA), either azacitidine or decitabine, was associated in 49 efficacy-evaluable patients with a 71% rate of composite complete remission (CR) and complete remission with incomplete recovery of counts (CRi), reported Dr. Amir Fathi from the Massachusetts General Hospital Cancer Center in Boston.

“This high remission rate in this traditionally high risk group and difficult to treat population is very compelling. Response rates were higher, and were achieved more quickly than would be expected from historical data associated with HMA therapy alone,” he said at a briefing at the annual congress of the European Hematology Association.

Many older patients with AML may not be able to withstand the rigors of cytotoxic chemotherapy, and these patients are often treated with hypomethylating agents or other low-intensity therapies, Dr. Fathi said.

Vadastuximab talirine is an antibody-drug conjugate designed to deliver a cytotoxic agent to myeloid leukemia cells, and in preclinical studies has been shown to enhance the cytotoxic effects of HMAs when given in combination.

Dr. Fathi reported preliminary data on 53 patients enrolled in a phase 1 study of the safety, tolerability, pharmacokinetics, and antileukemic activity of vadastuximab in combination with an HMA.

RTEmagicC_6a2ff6322f9166a4e0_Fathi_Amir_Boston.jpg.jpg

They enrolled adults with good performance status (Eastern Cooperative Oncology Group 0 or 1) who had CD33-positive AML and had declined intensive chemotherapy. They were given vadastuximab 10 mg/kg in an outpatient intravenous basis every 4 weeks on the fifth day of a 5-day HMA regimen,

Patients who were observed to have a clinical benefit could continue on treatment until relapse or unacceptable toxicity.

Of the 53 patients enrolled, 19 had adverse cytogenetic risk, and 30 had intermediate risk. The majority of patients (48) had not previously been treated for AML, and 5 had received prior low-intensity therapy for the myelodysplastic syndrome.

A total of 49 patients had sufficient data for the efficacy evaluation, and among these patients the composite CR/CRi rate was 71%; the rates of CR/CRi were similar whether the partner HMA was azacitadine or decitabine.

The overall response rate was 76%, with responses seem among higher-risk patients, including remissions in 16 of 22 patients with underlying myelodysplasia, and in 15 of 18 patients with adverse cytogenetics.

In addition, 8 of 19 patients with a CR, and 5 of 15 with a CRi met the definition for minimal residual disease.

Dr. Fathi reported early overall survival results, which he noted were still evolving. The estimated median overall survival for the first 25 patients enrolled in the study was 12.75 months after a median follow-up of 12.58 months.

The median relapse free-survival was 7.7 months. As of last follow-up, 27 patients were alive and remained on study.

The 30-day mortality rate was 2%, and the 60-day rate was 8%.

The most common treatment-related adverse events of any grade occurring in 20% or more of patients were fatigue, thrombocytopenia, nausea, febrile neutropenia, constipation, and anemia

The most common grade 3 or greater treatment-emergent adverse events were febrile neutropenia, thrombocytopenia, neutropenia, anemia, and fatigue.

In an interview, Dr. Fathi said that he has been very encouraged by the results thus far.

“This is a traditionally high-risk patient population. Even with a conventional induction cytotoxic chemotherapy, rates of remission in this population are relatively lower, so if the remission rates pan out in a larger population, I would say it competes and possibly supersedes what you would expect in an older population,” Dr. Fathi said.

Asked whether it might be possible to boost outcomes further with additional therapies, he said that “I’m not sure if there is much more improvement over what we are already seeing; a rate of 70-something percent among older adults with AML is quite good.”

“I like this ‘Trojan-horse’ approach to treating AML,” commented Dr. Anton Hagenbeek, professor of hematology at the Academic Medical Center, University of Amsterdam, who moderated the briefing.

A randomized phase III trial of vadastuximab talirine and HMA therapy is currently enrolling patients.

The study was funded by Seattle Genetics. Dr. Fathi reported no relevant disclosures.

Copenhagen – The experimental antibody-drug conjugate inotuzumab ozogamicin was associated with a nearly threefold higher complete remission rate than standard intensive chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia, investigators reported.

Among 218 patients in a phase III clinical trial, rates of combined complete remissions (CR) and complete remission with incomplete recovery of counts (CRi) were 80.7% for patients randomly assigned to receive the anti-CD22 conjugated antibody inotuzumab ozogamicin, compared with 29.4% for patients assigned to receive a standard intensive chemotherapy regimen chosen by investigators (P less than .001).

In addition, among patients who had complete remissions in both groups, significantly more patients in the inotuzumab ozogamicin group had fewer than .01% marrow blasts, a level below the threshold for minimal residual disease (MRD) (78.4% vs. 28.1%, respectively, P less than .001), reported Dr. Hagop Kantarjian, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston.

“In my opinion, inotuzumab is well tolerated with appropriate prevention measures, and my hope is that soon in the future, inotuzumab will be used not as a single agent, but in combination with chemotherapy or with other monoclonal antibodies targeting CD19,” he said at the annual congress of the European Hematology Association.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic.  CD22 is expressed on the surface of about 90% of B-cell ALL cells.

Dr. Daniel DeAngelo from the Dana-Farber Cancer Institute in Boston reported that in the same cohort of patients, the first 218 of 326 randomized in the INO-VATE trial, , the co-primary endpoint of CR/CRi by independent review was achieved by 80.7% of patients treated with inotuzumab and 33.3% treated with standard of care.The updated data presented at the meeting also are published online in the New England Journal of Medicine 2016 June doi:10.1056/NEJMoa1509277 .

The phase III trial randomized 326 patients with relapsed/refractory CD22-positive ALL due for salvage 1 or 2 therapy to inotuzumab or standard of care, consisting of either the FLAG regimen (fludarabine (Fludara)/cytarabine (Ara-C)/granulocyte colony-stimulating factor), Ara-C plus mitoxantrone (Novantrone), or high-dose Ara-C. The starting dose for inotuzumab was 1.8 mg/m²/cycle and was reduced to 1.5 mg/m²/cycle once a CR or CRi was achieved. Patients were stratified by duration of first remission, salvage 1 or 2, and age.

The first 218 randomized patients were included in the intention-to-treat CR/CRi analysis, which was modified after excluding 13 patients who refused to start treatment, all in the standard-of-care arm.

The patients’ median age was 47 years (ranging up to 79 years), two-thirds were in salvage 1, and more than half had a remission duration of less than 12 months, an adverse prognostic feature.

Dr. Kantarjian reported that in addition to the superior remission rates seen with inotuzumab ozogamicin, patients on the antibody-drug conjugate had significantly longer duration of remissions, at a median of 4.6 months vs. 3.1 months for patients on chemotherapy (P = .003).

An intention-to-treat survival analysis including all 326 patients randomized in the trial showed that progression-free survival was significantly longer in the inotuzumab ozogamicin group, at a median of 5.0 vs. 1.8 months (hazard ratio .45 P less than .001).

RTEmagicC_5a459f2cdbdd4063bc_Izraeli_Shai_Israel.jpg.jpg

Overall survival was slightly better with inotuzumab, at a median of 7.7 months vs. 6.7 months, but this did not meet the study definition of significantly improved overall survival with a pre-specified boundary of P = .014 or lower.

In the safety population, which included 139 patients assigned to inotuzumab and 120 to chemotherapy who had received at least one dose of the assigned regimen before data cutoff, the most frequent grade 3 or higher non-hematologic adverse events with inotuzumab ozogamicin were liver-related. In all, 13% of patients assigned to inotuzumab in the safety population developed veno-occlusive liver disease of any grade, compared with 1% of those assigned to standard of care.

“This drug showed consistently high activity in several studies, so I think it’s very exciting, The real challenge will be how to proceed, how to incorporate it into clinical trials both in pediatrics and adults,” commented Dr. Shai Izraeli, head of the section of functional genomics and childhood leukemia and cancer research at Sheba Medical Center in Ramat Gan, Israel. Dr. Izraeli was co-moderator of the late-breaking abstract session where the data were presented, but was not involved in the study.

He said in an interview that the challenge for investigators will be to develop clinical trials that combine this agent with different immunotherapies from different companies, which would be a logistical nightmare, “but I think we need to do it.”

The study was funded by Pfizer. Dr. Kantarjian disclosed research support from the company. Dr. Izraeli reported having no relevant disclosures.

Copenhagen – The experimental antibody-drug conjugate inotuzumab ozogamicin was associated with a nearly threefold higher complete remission rate than standard intensive chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia, investigators reported.

Among 218 patients in a phase III clinical trial, rates of combined complete remissions (CR) and complete remission with incomplete recovery of counts (CRi) were 80.7% for patients randomly assigned to receive the anti-CD22 conjugated antibody inotuzumab ozogamicin, compared with 29.4% for patients assigned to receive a standard intensive chemotherapy regimen chosen by investigators (P less than .001).

In addition, among patients who had complete remissions in both groups, significantly more patients in the inotuzumab ozogamicin group had fewer than .01% marrow blasts, a level below the threshold for minimal residual disease (MRD) (78.4% vs. 28.1%, respectively, P less than .001), reported Dr. Hagop Kantarjian, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston.

“In my opinion, inotuzumab is well tolerated with appropriate prevention measures, and my hope is that soon in the future, inotuzumab will be used not as a single agent, but in combination with chemotherapy or with other monoclonal antibodies targeting CD19,” he said at the annual congress of the European Hematology Association.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic.  CD22 is expressed on the surface of about 90% of B-cell ALL cells.

Dr. Daniel DeAngelo from the Dana-Farber Cancer Institute in Boston reported that in the same cohort of patients, the first 218 of 326 randomized in the INO-VATE trial, , the co-primary endpoint of CR/CRi by independent review was achieved by 80.7% of patients treated with inotuzumab and 33.3% treated with standard of care.The updated data presented at the meeting also are published online in the New England Journal of Medicine 2016 June doi:10.1056/NEJMoa1509277 .

The phase III trial randomized 326 patients with relapsed/refractory CD22-positive ALL due for salvage 1 or 2 therapy to inotuzumab or standard of care, consisting of either the FLAG regimen (fludarabine (Fludara)/cytarabine (Ara-C)/granulocyte colony-stimulating factor), Ara-C plus mitoxantrone (Novantrone), or high-dose Ara-C. The starting dose for inotuzumab was 1.8 mg/m²/cycle and was reduced to 1.5 mg/m²/cycle once a CR or CRi was achieved. Patients were stratified by duration of first remission, salvage 1 or 2, and age.

The first 218 randomized patients were included in the intention-to-treat CR/CRi analysis, which was modified after excluding 13 patients who refused to start treatment, all in the standard-of-care arm.

The patients’ median age was 47 years (ranging up to 79 years), two-thirds were in salvage 1, and more than half had a remission duration of less than 12 months, an adverse prognostic feature.

Dr. Kantarjian reported that in addition to the superior remission rates seen with inotuzumab ozogamicin, patients on the antibody-drug conjugate had significantly longer duration of remissions, at a median of 4.6 months vs. 3.1 months for patients on chemotherapy (P = .003).

An intention-to-treat survival analysis including all 326 patients randomized in the trial showed that progression-free survival was significantly longer in the inotuzumab ozogamicin group, at a median of 5.0 vs. 1.8 months (hazard ratio .45 P less than .001).

RTEmagicC_5a459f2cdbdd4063bc_Izraeli_Shai_Israel.jpg.jpg

Overall survival was slightly better with inotuzumab, at a median of 7.7 months vs. 6.7 months, but this did not meet the study definition of significantly improved overall survival with a pre-specified boundary of P = .014 or lower.

In the safety population, which included 139 patients assigned to inotuzumab and 120 to chemotherapy who had received at least one dose of the assigned regimen before data cutoff, the most frequent grade 3 or higher non-hematologic adverse events with inotuzumab ozogamicin were liver-related. In all, 13% of patients assigned to inotuzumab in the safety population developed veno-occlusive liver disease of any grade, compared with 1% of those assigned to standard of care.

“This drug showed consistently high activity in several studies, so I think it’s very exciting, The real challenge will be how to proceed, how to incorporate it into clinical trials both in pediatrics and adults,” commented Dr. Shai Izraeli, head of the section of functional genomics and childhood leukemia and cancer research at Sheba Medical Center in Ramat Gan, Israel. Dr. Izraeli was co-moderator of the late-breaking abstract session where the data were presented, but was not involved in the study.

He said in an interview that the challenge for investigators will be to develop clinical trials that combine this agent with different immunotherapies from different companies, which would be a logistical nightmare, “but I think we need to do it.”

The study was funded by Pfizer. Dr. Kantarjian disclosed research support from the company. Dr. Izraeli reported having no relevant disclosures.

Copenhagen – The experimental antibody-drug conjugate inotuzumab ozogamicin was associated with a nearly threefold higher complete remission rate than standard intensive chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia, investigators reported.

Among 218 patients in a phase III clinical trial, rates of combined complete remissions (CR) and complete remission with incomplete recovery of counts (CRi) were 80.7% for patients randomly assigned to receive the anti-CD22 conjugated antibody inotuzumab ozogamicin, compared with 29.4% for patients assigned to receive a standard intensive chemotherapy regimen chosen by investigators (P less than .001).

In addition, among patients who had complete remissions in both groups, significantly more patients in the inotuzumab ozogamicin group had fewer than .01% marrow blasts, a level below the threshold for minimal residual disease (MRD) (78.4% vs. 28.1%, respectively, P less than .001), reported Dr. Hagop Kantarjian, professor in the department of leukemia at the University of Texas MD Anderson Cancer Center, Houston.

“In my opinion, inotuzumab is well tolerated with appropriate prevention measures, and my hope is that soon in the future, inotuzumab will be used not as a single agent, but in combination with chemotherapy or with other monoclonal antibodies targeting CD19,” he said at the annual congress of the European Hematology Association.

Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic.  CD22 is expressed on the surface of about 90% of B-cell ALL cells.

Dr. Daniel DeAngelo from the Dana-Farber Cancer Institute in Boston reported that in the same cohort of patients, the first 218 of 326 randomized in the INO-VATE trial, , the co-primary endpoint of CR/CRi by independent review was achieved by 80.7% of patients treated with inotuzumab and 33.3% treated with standard of care.The updated data presented at the meeting also are published online in the New England Journal of Medicine 2016 June doi:10.1056/NEJMoa1509277 .

The phase III trial randomized 326 patients with relapsed/refractory CD22-positive ALL due for salvage 1 or 2 therapy to inotuzumab or standard of care, consisting of either the FLAG regimen (fludarabine (Fludara)/cytarabine (Ara-C)/granulocyte colony-stimulating factor), Ara-C plus mitoxantrone (Novantrone), or high-dose Ara-C. The starting dose for inotuzumab was 1.8 mg/m²/cycle and was reduced to 1.5 mg/m²/cycle once a CR or CRi was achieved. Patients were stratified by duration of first remission, salvage 1 or 2, and age.

The first 218 randomized patients were included in the intention-to-treat CR/CRi analysis, which was modified after excluding 13 patients who refused to start treatment, all in the standard-of-care arm.

The patients’ median age was 47 years (ranging up to 79 years), two-thirds were in salvage 1, and more than half had a remission duration of less than 12 months, an adverse prognostic feature.

Dr. Kantarjian reported that in addition to the superior remission rates seen with inotuzumab ozogamicin, patients on the antibody-drug conjugate had significantly longer duration of remissions, at a median of 4.6 months vs. 3.1 months for patients on chemotherapy (P = .003).

An intention-to-treat survival analysis including all 326 patients randomized in the trial showed that progression-free survival was significantly longer in the inotuzumab ozogamicin group, at a median of 5.0 vs. 1.8 months (hazard ratio .45 P less than .001).

RTEmagicC_5a459f2cdbdd4063bc_Izraeli_Shai_Israel.jpg.jpg

Overall survival was slightly better with inotuzumab, at a median of 7.7 months vs. 6.7 months, but this did not meet the study definition of significantly improved overall survival with a pre-specified boundary of P = .014 or lower.

In the safety population, which included 139 patients assigned to inotuzumab and 120 to chemotherapy who had received at least one dose of the assigned regimen before data cutoff, the most frequent grade 3 or higher non-hematologic adverse events with inotuzumab ozogamicin were liver-related. In all, 13% of patients assigned to inotuzumab in the safety population developed veno-occlusive liver disease of any grade, compared with 1% of those assigned to standard of care.

“This drug showed consistently high activity in several studies, so I think it’s very exciting, The real challenge will be how to proceed, how to incorporate it into clinical trials both in pediatrics and adults,” commented Dr. Shai Izraeli, head of the section of functional genomics and childhood leukemia and cancer research at Sheba Medical Center in Ramat Gan, Israel. Dr. Izraeli was co-moderator of the late-breaking abstract session where the data were presented, but was not involved in the study.

He said in an interview that the challenge for investigators will be to develop clinical trials that combine this agent with different immunotherapies from different companies, which would be a logistical nightmare, “but I think we need to do it.”

The study was funded by Pfizer. Dr. Kantarjian disclosed research support from the company. Dr. Izraeli reported having no relevant disclosures.

Copenhagen – A real-life comparison of major bleeding risk with anticoagulants showed that in-hospital mortality was lower with novel oral agents than with vitamin K antagonists, but the risk varied by bleeding site.

Novel oral anticoagulants (NOACs) such as dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) were associated in randomized phase III clinical trials with lower incidences of major bleeding than vitamin K antagonists (VKA) such as warfarin, and the newer, heavily advertised agents are widely used in clinical practice, noted Dr. Laura Franco of the Stroke Unit at the University of Perugia, Italy.

“But there is [little] information about the management and outcomes of major bleeding with NOACs in real life,” she said at a briefing at the annual congress of the European Hematology Association.

RTEmagicC_060d36d5e9253802ad_Franco_Laura_Italy.jpg.jpg

To rectify this situation, Dr. Franco and her colleagues at nine Italian hospitals and the NOAC registry based in Dresden, Germany, looked at 30-day mortality and other outcomes among 874 consecutive patients admitted for a major bleeding episode from September 2013 through May 2016. In all, 220 of the patients were on NOACs, and 654 were on VKAs.

Intracranial bleeds occurred in 44% of all patients, but were significantly less common among patients on NOACs than on VKAs (22% vs, 52%, respectively, odds ratio 0.26, P less than .001), whereas gastrointestinal bleeds, which occurred in 30% of all patients, were more frequent with the newer oral agents than with the older VKAs (46% vs. 30%, OR 2.69, P less than .001).

Deaths within 30 days of emergency department admission were less frequent with NOACs (10% vs. 17%, hazard ratio 0.56, P = .012).

“But when we analyzed the subpopulation of patients with different sites of bleeding, we saw that among intracranial hemorrhage, the rate was equal among NOAC and VKAs patients, 25% in both groups,” Dr. Franco said.

Deaths from gastrointestinal bleeding were numerically lower among patients on NOACs (7% vs. 10%), but this difference was not statistically significant.

“The great advantages of the new oral anticoagulants are the reduced risk in intracranial hemorrhage, so we showed that the lower mortality is not due to an intrinsic capacity to reduce deaths by NOACs as compared to VKAs, but to a different pattern of bleeding sites,” Dr. Franco said.

The study funding source was not disclosed. Dr. Franco did not report relevant disclosures.

Copenhagen – A real-life comparison of major bleeding risk with anticoagulants showed that in-hospital mortality was lower with novel oral agents than with vitamin K antagonists, but the risk varied by bleeding site.

Novel oral anticoagulants (NOACs) such as dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) were associated in randomized phase III clinical trials with lower incidences of major bleeding than vitamin K antagonists (VKA) such as warfarin, and the newer, heavily advertised agents are widely used in clinical practice, noted Dr. Laura Franco of the Stroke Unit at the University of Perugia, Italy.

“But there is [little] information about the management and outcomes of major bleeding with NOACs in real life,” she said at a briefing at the annual congress of the European Hematology Association.

RTEmagicC_060d36d5e9253802ad_Franco_Laura_Italy.jpg.jpg

To rectify this situation, Dr. Franco and her colleagues at nine Italian hospitals and the NOAC registry based in Dresden, Germany, looked at 30-day mortality and other outcomes among 874 consecutive patients admitted for a major bleeding episode from September 2013 through May 2016. In all, 220 of the patients were on NOACs, and 654 were on VKAs.

Intracranial bleeds occurred in 44% of all patients, but were significantly less common among patients on NOACs than on VKAs (22% vs, 52%, respectively, odds ratio 0.26, P less than .001), whereas gastrointestinal bleeds, which occurred in 30% of all patients, were more frequent with the newer oral agents than with the older VKAs (46% vs. 30%, OR 2.69, P less than .001).

Deaths within 30 days of emergency department admission were less frequent with NOACs (10% vs. 17%, hazard ratio 0.56, P = .012).

“But when we analyzed the subpopulation of patients with different sites of bleeding, we saw that among intracranial hemorrhage, the rate was equal among NOAC and VKAs patients, 25% in both groups,” Dr. Franco said.

Deaths from gastrointestinal bleeding were numerically lower among patients on NOACs (7% vs. 10%), but this difference was not statistically significant.

“The great advantages of the new oral anticoagulants are the reduced risk in intracranial hemorrhage, so we showed that the lower mortality is not due to an intrinsic capacity to reduce deaths by NOACs as compared to VKAs, but to a different pattern of bleeding sites,” Dr. Franco said.

The study funding source was not disclosed. Dr. Franco did not report relevant disclosures.

Copenhagen – A real-life comparison of major bleeding risk with anticoagulants showed that in-hospital mortality was lower with novel oral agents than with vitamin K antagonists, but the risk varied by bleeding site.

Novel oral anticoagulants (NOACs) such as dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis) were associated in randomized phase III clinical trials with lower incidences of major bleeding than vitamin K antagonists (VKA) such as warfarin, and the newer, heavily advertised agents are widely used in clinical practice, noted Dr. Laura Franco of the Stroke Unit at the University of Perugia, Italy.

“But there is [little] information about the management and outcomes of major bleeding with NOACs in real life,” she said at a briefing at the annual congress of the European Hematology Association.

RTEmagicC_060d36d5e9253802ad_Franco_Laura_Italy.jpg.jpg

To rectify this situation, Dr. Franco and her colleagues at nine Italian hospitals and the NOAC registry based in Dresden, Germany, looked at 30-day mortality and other outcomes among 874 consecutive patients admitted for a major bleeding episode from September 2013 through May 2016. In all, 220 of the patients were on NOACs, and 654 were on VKAs.

Intracranial bleeds occurred in 44% of all patients, but were significantly less common among patients on NOACs than on VKAs (22% vs, 52%, respectively, odds ratio 0.26, P less than .001), whereas gastrointestinal bleeds, which occurred in 30% of all patients, were more frequent with the newer oral agents than with the older VKAs (46% vs. 30%, OR 2.69, P less than .001).

Deaths within 30 days of emergency department admission were less frequent with NOACs (10% vs. 17%, hazard ratio 0.56, P = .012).

“But when we analyzed the subpopulation of patients with different sites of bleeding, we saw that among intracranial hemorrhage, the rate was equal among NOAC and VKAs patients, 25% in both groups,” Dr. Franco said.

Deaths from gastrointestinal bleeding were numerically lower among patients on NOACs (7% vs. 10%), but this difference was not statistically significant.

“The great advantages of the new oral anticoagulants are the reduced risk in intracranial hemorrhage, so we showed that the lower mortality is not due to an intrinsic capacity to reduce deaths by NOACs as compared to VKAs, but to a different pattern of bleeding sites,” Dr. Franco said.

The study funding source was not disclosed. Dr. Franco did not report relevant disclosures.

Copenhagen – Investigators in Italy have found that a recently identified form of inherited thrombocytopenia related to mutations in the gene ETV6 (ETV6-RT) appears to be largely asymptomatic, but puts patients at significantly increased risk for hematologic malignancies, particularly childhood B-cell acute lymphoblastic leukemia (ALL).

“When we are talking about ETV6-related thrombocytopenia patients, we must pay more attention to this hidden but very dangerous risk of developing blood cancer – so that we can define prognosis and plan a personalized follow-up – [rather] than to bleeding complications, which are rare and usually do not affect the quality of life,” said Dr. Federica Melazzini from the University of Pavia, Italy.

RTEmagicC_d17a70f3894f095964_Melazzini_Federica_Italy.jpg.jpg

At a briefing at the annual congress of the European Hematology Association, Dr. Melazzini described a prospective study of the clinical and laboratory features of the newly identified disorder, with a focus on its association with hematologic cancers.

They enrolled 130 unrelated consecutive patients with inherited thrombocytopenias (IT) who did not have definitive diagnoses because they did exhibit criteria for any of the known forms of IT.

The investigators used whole exome sequencing or Sanger sequencing to look for mutations in ETV6, and when a mutation was identified, all available relatives of the affected participant (proband) also were evaluated. The authors also included data on five patients from two families known to have ETV6-RT from previous studies.

The participants were evaluated with complete blood counts, platelet sizing, flow cytometry studies of platelet membrane glycoproteins, as well as platelet aggregation, activation, adhesion and spreading. Other evaluations included differentiation of human megakaryocytes, morphological analysis of megakaryocytes, megakaryocytes flow cytometry, and evaluation of pro-platelet formation by megakaryocytes differentiated in vitro.

The investigators identified a total of 20 patients from 7 families bearing 5 different mutations in ETV6. Although these patients had only mild thrombocytopenias and a low bleeding tendency, 4 of the 20 had childhood ALL, supporting the association between ETV6 mutations and early leukemic transformation.

This translated into an incidence rate for hematologic malignancies of nearly 1 in 100 persons per year, compared with 1 in 10,000 per year in the general population, Dr. Melazzini said.

The investigators also noted that one patient developed Janus kinase 2 (JAK2)-positive polycythemia vera at age 37 years, “suggesting that this disease should be added to the list of malignancies to which the ETV6-RT predisposes.”

Dr. Melazzini said that clinicians should suspect ETV6-RT when a patient presents with an autosomal inherited thrombocytopenia without platelet macrocytosis, and should confirm the diagnosis with genetic analysis.

Patients also should be followed with whole blood cell counts and peripheral blood smear evaluations every 6-12 months, she recommended.

Dr Anton Hagenbeek, professor of hematology at the University of Amsterdam, who moderated the briefing but was not involved in the study, asked how clinicians should communicate the increased risk of hematologic malignancies to the patients.

Dr. Melazzini replied that patients need counseling about the risks of developing ALL or of passing on the trait if they plan to have children. Additionally, if patients develop ALL, the family should be cautioned against using a related donor for any allogeneic stem cell transplants, she said.

The study funding source was not disclosed. Dr. Melazzini and Dr. Hagenbeek reported no relevant disclosures.

Copenhagen – Investigators in Italy have found that a recently identified form of inherited thrombocytopenia related to mutations in the gene ETV6 (ETV6-RT) appears to be largely asymptomatic, but puts patients at significantly increased risk for hematologic malignancies, particularly childhood B-cell acute lymphoblastic leukemia (ALL).

“When we are talking about ETV6-related thrombocytopenia patients, we must pay more attention to this hidden but very dangerous risk of developing blood cancer – so that we can define prognosis and plan a personalized follow-up – [rather] than to bleeding complications, which are rare and usually do not affect the quality of life,” said Dr. Federica Melazzini from the University of Pavia, Italy.

RTEmagicC_d17a70f3894f095964_Melazzini_Federica_Italy.jpg.jpg

At a briefing at the annual congress of the European Hematology Association, Dr. Melazzini described a prospective study of the clinical and laboratory features of the newly identified disorder, with a focus on its association with hematologic cancers.

They enrolled 130 unrelated consecutive patients with inherited thrombocytopenias (IT) who did not have definitive diagnoses because they did exhibit criteria for any of the known forms of IT.

The investigators used whole exome sequencing or Sanger sequencing to look for mutations in ETV6, and when a mutation was identified, all available relatives of the affected participant (proband) also were evaluated. The authors also included data on five patients from two families known to have ETV6-RT from previous studies.

The participants were evaluated with complete blood counts, platelet sizing, flow cytometry studies of platelet membrane glycoproteins, as well as platelet aggregation, activation, adhesion and spreading. Other evaluations included differentiation of human megakaryocytes, morphological analysis of megakaryocytes, megakaryocytes flow cytometry, and evaluation of pro-platelet formation by megakaryocytes differentiated in vitro.

The investigators identified a total of 20 patients from 7 families bearing 5 different mutations in ETV6. Although these patients had only mild thrombocytopenias and a low bleeding tendency, 4 of the 20 had childhood ALL, supporting the association between ETV6 mutations and early leukemic transformation.

This translated into an incidence rate for hematologic malignancies of nearly 1 in 100 persons per year, compared with 1 in 10,000 per year in the general population, Dr. Melazzini said.

The investigators also noted that one patient developed Janus kinase 2 (JAK2)-positive polycythemia vera at age 37 years, “suggesting that this disease should be added to the list of malignancies to which the ETV6-RT predisposes.”

Dr. Melazzini said that clinicians should suspect ETV6-RT when a patient presents with an autosomal inherited thrombocytopenia without platelet macrocytosis, and should confirm the diagnosis with genetic analysis.

Patients also should be followed with whole blood cell counts and peripheral blood smear evaluations every 6-12 months, she recommended.

Dr Anton Hagenbeek, professor of hematology at the University of Amsterdam, who moderated the briefing but was not involved in the study, asked how clinicians should communicate the increased risk of hematologic malignancies to the patients.

Dr. Melazzini replied that patients need counseling about the risks of developing ALL or of passing on the trait if they plan to have children. Additionally, if patients develop ALL, the family should be cautioned against using a related donor for any allogeneic stem cell transplants, she said.

The study funding source was not disclosed. Dr. Melazzini and Dr. Hagenbeek reported no relevant disclosures.

Copenhagen – Investigators in Italy have found that a recently identified form of inherited thrombocytopenia related to mutations in the gene ETV6 (ETV6-RT) appears to be largely asymptomatic, but puts patients at significantly increased risk for hematologic malignancies, particularly childhood B-cell acute lymphoblastic leukemia (ALL).

“When we are talking about ETV6-related thrombocytopenia patients, we must pay more attention to this hidden but very dangerous risk of developing blood cancer – so that we can define prognosis and plan a personalized follow-up – [rather] than to bleeding complications, which are rare and usually do not affect the quality of life,” said Dr. Federica Melazzini from the University of Pavia, Italy.

RTEmagicC_d17a70f3894f095964_Melazzini_Federica_Italy.jpg.jpg

At a briefing at the annual congress of the European Hematology Association, Dr. Melazzini described a prospective study of the clinical and laboratory features of the newly identified disorder, with a focus on its association with hematologic cancers.

They enrolled 130 unrelated consecutive patients with inherited thrombocytopenias (IT) who did not have definitive diagnoses because they did exhibit criteria for any of the known forms of IT.

The investigators used whole exome sequencing or Sanger sequencing to look for mutations in ETV6, and when a mutation was identified, all available relatives of the affected participant (proband) also were evaluated. The authors also included data on five patients from two families known to have ETV6-RT from previous studies.

The participants were evaluated with complete blood counts, platelet sizing, flow cytometry studies of platelet membrane glycoproteins, as well as platelet aggregation, activation, adhesion and spreading. Other evaluations included differentiation of human megakaryocytes, morphological analysis of megakaryocytes, megakaryocytes flow cytometry, and evaluation of pro-platelet formation by megakaryocytes differentiated in vitro.

The investigators identified a total of 20 patients from 7 families bearing 5 different mutations in ETV6. Although these patients had only mild thrombocytopenias and a low bleeding tendency, 4 of the 20 had childhood ALL, supporting the association between ETV6 mutations and early leukemic transformation.

This translated into an incidence rate for hematologic malignancies of nearly 1 in 100 persons per year, compared with 1 in 10,000 per year in the general population, Dr. Melazzini said.

The investigators also noted that one patient developed Janus kinase 2 (JAK2)-positive polycythemia vera at age 37 years, “suggesting that this disease should be added to the list of malignancies to which the ETV6-RT predisposes.”

Dr. Melazzini said that clinicians should suspect ETV6-RT when a patient presents with an autosomal inherited thrombocytopenia without platelet macrocytosis, and should confirm the diagnosis with genetic analysis.

Patients also should be followed with whole blood cell counts and peripheral blood smear evaluations every 6-12 months, she recommended.

Dr Anton Hagenbeek, professor of hematology at the University of Amsterdam, who moderated the briefing but was not involved in the study, asked how clinicians should communicate the increased risk of hematologic malignancies to the patients.

Dr. Melazzini replied that patients need counseling about the risks of developing ALL or of passing on the trait if they plan to have children. Additionally, if patients develop ALL, the family should be cautioned against using a related donor for any allogeneic stem cell transplants, she said.

The study funding source was not disclosed. Dr. Melazzini and Dr. Hagenbeek reported no relevant disclosures.

Copenhagen – Relapse of acute myeloid leukemia among older adults may be caused by pre-leukemic stem cells lurking after treatment.

Among 107 adults with AML treated in a German multicenter clinical trial, 36% were found to have pre-treatment mutations that persisted after therapy, reported Dr. Klaus Metzeler of the University of Munich.

“Mutation persistence after chemotherapy was way more common in older patients, and importantly, patients with persisting mutations had a significantly higher risk of AML recurrence,” he said at a briefing prior to presentation of the data at the annual congress of the European Hematology Association.

RTEmagicC_d4be0d4cf497ee4a5a_Metzeler_Klaus_Munich.jpg.jpg

The higher relapse risk associated with persistent mutations remained even after adjustment for patient age, cytogenetics, and other risk factors, he noted.

AML can arise from a clone of pre-leukemic stem cells, and it is known that pre-leukemic clones carry genetic mutations that can later be found in leukemic cells. The investigators hypothesized that pre-leukemic clones persisting after chemotherapy could be related treatment outcomes and survival.

To test this idea, they analyzed samples collected from bone marrow or peripheral blood of 107 adults with AML (median age 53 years, range 20-80 years) both before chemotherapy and during the first remission. The majority of remission samples (92%) were collected within the first 180 days of remission.

The investigators looked for the presence of 68 genes known to be recurrently mutated in myeloid malignancies, and identified any sequence alterations with a variant allele frequency of 2% or greater as either known or possible driver mutations, variants of unknown significance, or known germline polymorphisms.

A total of 426 driver mutations in 42 genes were detected in samples collected at diagnosis. In all, 69 patients (64%) had no mutations following chemotherapy. Among the remaining 38 patients, there were 66 persistent mutations in 15 genes. The most common persistent mutations were in the genes DNMT3A, TET2, SRF2, and ASXL1.

“Those are precisely those mutations that are known to occur in these pre-leukemic clones,” Dr. Metzeler said.

Mutations found in the pre-treatment but not the remission samples included those in NMP1, FLT3, WT1, and NRAS.

As noted, patients with one or more persistent mutations tended to be older than those with no mutations, with a median age of 63 years vs. 48 years (P less than .001). Persistence of one or more driver mutations in remission was associated with both significantly shorter relapse-free survival (median 14.3 months vs. 58.0 months, P = .009) and shorter overall survival (median, 39.6 months vs. more than 72 months; P = .005).

In multivariate analyses controlling for age, European LeukemiaNet genetic risk groups, and remission status (complete remission vs. complete remission with incomplete recovery of counts), any persistent mutations was associated with significantly worse relapse-free survival (hazard ratio, 2.2, P =.02) and overall survival (HR, 3.0, P = .008). 

“It is well known that older AML patients have a poor prognosis, but the reasons for that aren’t fully understood yet. So the hypothesis that would come from our data is that frequent persistence of pre-leukemic clones may be one potential explanation for the higher relapse risk that we found in older patients,” Dr. Metzeler said.

Asked how clinicians might go about targeting the escaped mutations, Dr. Metzeler noted that the incidence of pre-leukemic somatic mutations among healthy 70-year-olds is about 10%.

“So the challenge will be to identify those patients who will actually relapse, and then an option in fit patients would be an allogeneic transplant. We don’t have targeted agents at the moment where we can target these specific mutations, and it would be relatively hard to justify giving those patients additional chemotherapy at this point,” he said.

RTEmagicC_d4be0d4cf497ee4a5a_Green_Tony_Cambridge.jpg.jpg

“What this is showing for the first time is a clue as to why a subset will relapse, and now we know that this group exists with these pre-leukemic clones, we can begin to ask questions about why it is they relapse or don’t relapse. Is it something to do with the immune system in those patients who don’t relapse?” commented EHA president Tony Green, M.D., who was not involved in the study, but attended the briefing. Dr. Green is a professor in the department of hematology at the Cambridge Stem Cell Institute, University of Cambridge, U.K.

The study was funded by European Hematology Association research fellowships. Dr. Metzeler and Dr. Green reported no relevant disclosures.

Copenhagen – Relapse of acute myeloid leukemia among older adults may be caused by pre-leukemic stem cells lurking after treatment.

Among 107 adults with AML treated in a German multicenter clinical trial, 36% were found to have pre-treatment mutations that persisted after therapy, reported Dr. Klaus Metzeler of the University of Munich.

“Mutation persistence after chemotherapy was way more common in older patients, and importantly, patients with persisting mutations had a significantly higher risk of AML recurrence,” he said at a briefing prior to presentation of the data at the annual congress of the European Hematology Association.

RTEmagicC_d4be0d4cf497ee4a5a_Metzeler_Klaus_Munich.jpg.jpg

The higher relapse risk associated with persistent mutations remained even after adjustment for patient age, cytogenetics, and other risk factors, he noted.

AML can arise from a clone of pre-leukemic stem cells, and it is known that pre-leukemic clones carry genetic mutations that can later be found in leukemic cells. The investigators hypothesized that pre-leukemic clones persisting after chemotherapy could be related treatment outcomes and survival.

To test this idea, they analyzed samples collected from bone marrow or peripheral blood of 107 adults with AML (median age 53 years, range 20-80 years) both before chemotherapy and during the first remission. The majority of remission samples (92%) were collected within the first 180 days of remission.

The investigators looked for the presence of 68 genes known to be recurrently mutated in myeloid malignancies, and identified any sequence alterations with a variant allele frequency of 2% or greater as either known or possible driver mutations, variants of unknown significance, or known germline polymorphisms.

A total of 426 driver mutations in 42 genes were detected in samples collected at diagnosis. In all, 69 patients (64%) had no mutations following chemotherapy. Among the remaining 38 patients, there were 66 persistent mutations in 15 genes. The most common persistent mutations were in the genes DNMT3A, TET2, SRF2, and ASXL1.

“Those are precisely those mutations that are known to occur in these pre-leukemic clones,” Dr. Metzeler said.

Mutations found in the pre-treatment but not the remission samples included those in NMP1, FLT3, WT1, and NRAS.

As noted, patients with one or more persistent mutations tended to be older than those with no mutations, with a median age of 63 years vs. 48 years (P less than .001). Persistence of one or more driver mutations in remission was associated with both significantly shorter relapse-free survival (median 14.3 months vs. 58.0 months, P = .009) and shorter overall survival (median, 39.6 months vs. more than 72 months; P = .005).

In multivariate analyses controlling for age, European LeukemiaNet genetic risk groups, and remission status (complete remission vs. complete remission with incomplete recovery of counts), any persistent mutations was associated with significantly worse relapse-free survival (hazard ratio, 2.2, P =.02) and overall survival (HR, 3.0, P = .008). 

“It is well known that older AML patients have a poor prognosis, but the reasons for that aren’t fully understood yet. So the hypothesis that would come from our data is that frequent persistence of pre-leukemic clones may be one potential explanation for the higher relapse risk that we found in older patients,” Dr. Metzeler said.

Asked how clinicians might go about targeting the escaped mutations, Dr. Metzeler noted that the incidence of pre-leukemic somatic mutations among healthy 70-year-olds is about 10%.

“So the challenge will be to identify those patients who will actually relapse, and then an option in fit patients would be an allogeneic transplant. We don’t have targeted agents at the moment where we can target these specific mutations, and it would be relatively hard to justify giving those patients additional chemotherapy at this point,” he said.

RTEmagicC_d4be0d4cf497ee4a5a_Green_Tony_Cambridge.jpg.jpg

“What this is showing for the first time is a clue as to why a subset will relapse, and now we know that this group exists with these pre-leukemic clones, we can begin to ask questions about why it is they relapse or don’t relapse. Is it something to do with the immune system in those patients who don’t relapse?” commented EHA president Tony Green, M.D., who was not involved in the study, but attended the briefing. Dr. Green is a professor in the department of hematology at the Cambridge Stem Cell Institute, University of Cambridge, U.K.

The study was funded by European Hematology Association research fellowships. Dr. Metzeler and Dr. Green reported no relevant disclosures.

Copenhagen – Relapse of acute myeloid leukemia among older adults may be caused by pre-leukemic stem cells lurking after treatment.

Among 107 adults with AML treated in a German multicenter clinical trial, 36% were found to have pre-treatment mutations that persisted after therapy, reported Dr. Klaus Metzeler of the University of Munich.

“Mutation persistence after chemotherapy was way more common in older patients, and importantly, patients with persisting mutations had a significantly higher risk of AML recurrence,” he said at a briefing prior to presentation of the data at the annual congress of the European Hematology Association.

RTEmagicC_d4be0d4cf497ee4a5a_Metzeler_Klaus_Munich.jpg.jpg

The higher relapse risk associated with persistent mutations remained even after adjustment for patient age, cytogenetics, and other risk factors, he noted.

AML can arise from a clone of pre-leukemic stem cells, and it is known that pre-leukemic clones carry genetic mutations that can later be found in leukemic cells. The investigators hypothesized that pre-leukemic clones persisting after chemotherapy could be related treatment outcomes and survival.

To test this idea, they analyzed samples collected from bone marrow or peripheral blood of 107 adults with AML (median age 53 years, range 20-80 years) both before chemotherapy and during the first remission. The majority of remission samples (92%) were collected within the first 180 days of remission.

The investigators looked for the presence of 68 genes known to be recurrently mutated in myeloid malignancies, and identified any sequence alterations with a variant allele frequency of 2% or greater as either known or possible driver mutations, variants of unknown significance, or known germline polymorphisms.

A total of 426 driver mutations in 42 genes were detected in samples collected at diagnosis. In all, 69 patients (64%) had no mutations following chemotherapy. Among the remaining 38 patients, there were 66 persistent mutations in 15 genes. The most common persistent mutations were in the genes DNMT3A, TET2, SRF2, and ASXL1.

“Those are precisely those mutations that are known to occur in these pre-leukemic clones,” Dr. Metzeler said.

Mutations found in the pre-treatment but not the remission samples included those in NMP1, FLT3, WT1, and NRAS.

As noted, patients with one or more persistent mutations tended to be older than those with no mutations, with a median age of 63 years vs. 48 years (P less than .001). Persistence of one or more driver mutations in remission was associated with both significantly shorter relapse-free survival (median 14.3 months vs. 58.0 months, P = .009) and shorter overall survival (median, 39.6 months vs. more than 72 months; P = .005).

In multivariate analyses controlling for age, European LeukemiaNet genetic risk groups, and remission status (complete remission vs. complete remission with incomplete recovery of counts), any persistent mutations was associated with significantly worse relapse-free survival (hazard ratio, 2.2, P =.02) and overall survival (HR, 3.0, P = .008). 

“It is well known that older AML patients have a poor prognosis, but the reasons for that aren’t fully understood yet. So the hypothesis that would come from our data is that frequent persistence of pre-leukemic clones may be one potential explanation for the higher relapse risk that we found in older patients,” Dr. Metzeler said.

Asked how clinicians might go about targeting the escaped mutations, Dr. Metzeler noted that the incidence of pre-leukemic somatic mutations among healthy 70-year-olds is about 10%.

“So the challenge will be to identify those patients who will actually relapse, and then an option in fit patients would be an allogeneic transplant. We don’t have targeted agents at the moment where we can target these specific mutations, and it would be relatively hard to justify giving those patients additional chemotherapy at this point,” he said.

RTEmagicC_d4be0d4cf497ee4a5a_Green_Tony_Cambridge.jpg.jpg

“What this is showing for the first time is a clue as to why a subset will relapse, and now we know that this group exists with these pre-leukemic clones, we can begin to ask questions about why it is they relapse or don’t relapse. Is it something to do with the immune system in those patients who don’t relapse?” commented EHA president Tony Green, M.D., who was not involved in the study, but attended the briefing. Dr. Green is a professor in the department of hematology at the Cambridge Stem Cell Institute, University of Cambridge, U.K.

The study was funded by European Hematology Association research fellowships. Dr. Metzeler and Dr. Green reported no relevant disclosures.