EHA Congress 2017

MADRID – A four-drug induction regimen induced quicker and deeper remissions than sequential triplet regimens in patients with newly diagnosed multiple myeloma.

In addition, fast, deep remissions may lead to improved progression-free survival (PFS) following autologous stem cell transplantation (ASCT), said investigators from a U.K. Medical Research Council study.

In the phase 3 randomized, parallel group Myeloma XI study, very good partial responses (VGPR) or better were seen following induction in 79.5% of patients assigned to the quadruplet (KCRD) of carfilzomib (Kyprolis), cyclophosphamide, lenalidomide (Revlimid), and dexamethasone, compared with 60.8% for those assigned to cyclophosphamide, lenalidomide, and dexamethasone (CRD) and 52.8% for those assigned to cyclophosphamide, thalidomide, and dexamethasone (CTD), said Charlotte Pawlyn, MD, PhD, at the annual congress of the European Hematology Association.

“In our study, we see a very much deeper response after initial induction with the quadruplet regimen, compared with triplet regimens,” Dr. Pawlyn of the Institute of Cancer Research, London, said in an interview.

Medical Research Council investigators showed in the Myeloma IX study that among patients who had a less than VGPR to an immunomodulator-based triplet regimen such as CRD, a triplet regimen including the proteasome inhibitor bortezomib (Velcade) could improve both pre- and post-transplant response rates, and that the improved responses translated into improved PFS.

For the Myeloma XI study, the investigators employed the same response-adapted approach to compare outcomes following induction with the proteasome inhibitor–containing KCRD regimen and the lenalidomide- or thalidomide-based regimens.

Nancy B. Baron

[email protected]

MADRID – A four-drug induction regimen induced quicker and deeper remissions than sequential triplet regimens in patients with newly diagnosed multiple myeloma.

In addition, fast, deep remissions may lead to improved progression-free survival (PFS) following autologous stem cell transplantation (ASCT), said investigators from a U.K. Medical Research Council study.

In the phase 3 randomized, parallel group Myeloma XI study, very good partial responses (VGPR) or better were seen following induction in 79.5% of patients assigned to the quadruplet (KCRD) of carfilzomib (Kyprolis), cyclophosphamide, lenalidomide (Revlimid), and dexamethasone, compared with 60.8% for those assigned to cyclophosphamide, lenalidomide, and dexamethasone (CRD) and 52.8% for those assigned to cyclophosphamide, thalidomide, and dexamethasone (CTD), said Charlotte Pawlyn, MD, PhD, at the annual congress of the European Hematology Association.

“In our study, we see a very much deeper response after initial induction with the quadruplet regimen, compared with triplet regimens,” Dr. Pawlyn of the Institute of Cancer Research, London, said in an interview.

Medical Research Council investigators showed in the Myeloma IX study that among patients who had a less than VGPR to an immunomodulator-based triplet regimen such as CRD, a triplet regimen including the proteasome inhibitor bortezomib (Velcade) could improve both pre- and post-transplant response rates, and that the improved responses translated into improved PFS.

For the Myeloma XI study, the investigators employed the same response-adapted approach to compare outcomes following induction with the proteasome inhibitor–containing KCRD regimen and the lenalidomide- or thalidomide-based regimens.

Nancy B. Baron

[email protected]

MADRID – A four-drug induction regimen induced quicker and deeper remissions than sequential triplet regimens in patients with newly diagnosed multiple myeloma.

In addition, fast, deep remissions may lead to improved progression-free survival (PFS) following autologous stem cell transplantation (ASCT), said investigators from a U.K. Medical Research Council study.

In the phase 3 randomized, parallel group Myeloma XI study, very good partial responses (VGPR) or better were seen following induction in 79.5% of patients assigned to the quadruplet (KCRD) of carfilzomib (Kyprolis), cyclophosphamide, lenalidomide (Revlimid), and dexamethasone, compared with 60.8% for those assigned to cyclophosphamide, lenalidomide, and dexamethasone (CRD) and 52.8% for those assigned to cyclophosphamide, thalidomide, and dexamethasone (CTD), said Charlotte Pawlyn, MD, PhD, at the annual congress of the European Hematology Association.

“In our study, we see a very much deeper response after initial induction with the quadruplet regimen, compared with triplet regimens,” Dr. Pawlyn of the Institute of Cancer Research, London, said in an interview.

Medical Research Council investigators showed in the Myeloma IX study that among patients who had a less than VGPR to an immunomodulator-based triplet regimen such as CRD, a triplet regimen including the proteasome inhibitor bortezomib (Velcade) could improve both pre- and post-transplant response rates, and that the improved responses translated into improved PFS.

For the Myeloma XI study, the investigators employed the same response-adapted approach to compare outcomes following induction with the proteasome inhibitor–containing KCRD regimen and the lenalidomide- or thalidomide-based regimens.

Nancy B. Baron

[email protected]

Micrograph showing MM

MADRID—New research suggests one triplet regimen may be more active but also more toxic than another in patients with newly diagnosed multiple myeloma (MM).

In the FORTE trial, the combination of carfilzomib, lenalidomide, and dexamethasone (KRD) produced higher response rates than carfilzomib, cyclophosphamide, and dexamethasone (KCD).

However, treatment with KRD also produced significantly more grade 3/4 non-hematologic adverse events (AEs) and serious AEs than the KCD regimen.

Francesca Gay, MD, PhD, of University of Torino in Italy, presented these results, from a planned interim analysis of FORTE, at the 22nd Congress of the European Hematology Association (EHA) as abstract S410.

The trial enrolled 477 MM patients younger than 65 years of age.

The patients were randomized to receive:

• Four 28-day KCD cycles (n=154)

  Carfilzomib at 20 mg/m² (for cycles 1 and 2) or 36 mg/m² (for subsequent cycles) on days 1, 2, 8, 9, 15, and 16

  Cyclophosphamide at 300 mg/m² on days 1, 8, and 15

  Dexamethasone at 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23

• Four 28-day KRD cycles (n=309)

  Carfilzomib and dexamethasone as above

  Lenalidomide at 25 mg on days 1-21

After the fourth induction cycle, all patients received cyclophosphamide at 2 g/m², followed by peripheral blood stem cell (PBSC) collection for autologous stem cell transplant.

Patient characteristics

The median age was 57 (range, 52-62) in the KCD arm and the KRD arm (range, 51-62). In both arms, 55% of patients were male.

Roughly half of patients in both arms had an ISS stage of I (52% in the KCD arm and 51% in the KRD arm), 31% of patients in both arms were stage II, and 17% were stage III.

Fifty-eight percent of patients in the KCD arm and 59% in the KRD arm did not have t(4;14), t(14;16), or del17. Thirty-one percent and 26%, respectively, did have one of these cytogenetic abnormalities. (For the remaining patients, cytogenetic risk data were missing.)

PBSC mobilization and response

The median number of PBSCs collected was 8.6 x 10⁶/kg in the KCD arm and 6.3 x 10⁶/kg in the KRD arm. Plerixafor was required in 6% of patients in the KCD arm and 28% of patients in the KRD arm (P<0.001).

Ninety-two percent of patients in the KCD arm and 96% in the KRD arm had a partial response or better. Sixty-one percent and 74%, respectively, had a very good partial response (P=0.01). Six percent and 15%, respectively, had a complete response.

Safety

Grade 3/4 hematologic AEs and serious AEs (in the KRD and KCD arms, respectively) were thrombocytopenia (2% and 1%), neutropenia (6% and 5%), and anemia (2% and 3%). Seven percent of KRD patients and 6% of KCD patients had at least 1 grade 3/4 or serious hematologic AE.

Grade 3/4 non-hematologic AEs and serious AEs (in the KRD and KCD arms, respectively) included dermatologic events (8% and 1%, P<0.001), renal events (1% and 2%), fever (4% and 1%), infections (5% and 3%), gastrointestinal AEs (2% and 1%), hepatic events (8% and 1%, P<0.001), venous thromboembolism (1% and 0%), hypertension (3% and 2%), and cardiac events (1% and 2%).

Thirty-two percent of KRD patients and 16% of KCD patients had at least 1 grade 3/4 or serious non-hematologic AE (P<0.001).

Four percent of patients in the KRD arm and 2% in the KCD arm discontinued treatment due to AEs. Fifteen percent and 6%, respectively, reduced the dose of at least 1 drug (P=0.005).

One percent of patients in the KRD arm and 2% in the KCD arm died from AEs. In the KCD arm, 1 patient had a sudden death, and 1 died of pneumonia. In the KRD arm, there was 1 sudden death in a patient with sepsis, 1 patient died of infection, and 1 died of cardiac arrest (this patient previously discontinued treatment due to renal failure).

Micrograph showing MM

MADRID—New research suggests one triplet regimen may be more active but also more toxic than another in patients with newly diagnosed multiple myeloma (MM).

In the FORTE trial, the combination of carfilzomib, lenalidomide, and dexamethasone (KRD) produced higher response rates than carfilzomib, cyclophosphamide, and dexamethasone (KCD).

However, treatment with KRD also produced significantly more grade 3/4 non-hematologic adverse events (AEs) and serious AEs than the KCD regimen.

Francesca Gay, MD, PhD, of University of Torino in Italy, presented these results, from a planned interim analysis of FORTE, at the 22nd Congress of the European Hematology Association (EHA) as abstract S410.

The trial enrolled 477 MM patients younger than 65 years of age.

The patients were randomized to receive:

• Four 28-day KCD cycles (n=154)

  Carfilzomib at 20 mg/m² (for cycles 1 and 2) or 36 mg/m² (for subsequent cycles) on days 1, 2, 8, 9, 15, and 16

  Cyclophosphamide at 300 mg/m² on days 1, 8, and 15

  Dexamethasone at 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23

• Four 28-day KRD cycles (n=309)

  Carfilzomib and dexamethasone as above

  Lenalidomide at 25 mg on days 1-21

After the fourth induction cycle, all patients received cyclophosphamide at 2 g/m², followed by peripheral blood stem cell (PBSC) collection for autologous stem cell transplant.

Patient characteristics

The median age was 57 (range, 52-62) in the KCD arm and the KRD arm (range, 51-62). In both arms, 55% of patients were male.

Roughly half of patients in both arms had an ISS stage of I (52% in the KCD arm and 51% in the KRD arm), 31% of patients in both arms were stage II, and 17% were stage III.

Fifty-eight percent of patients in the KCD arm and 59% in the KRD arm did not have t(4;14), t(14;16), or del17. Thirty-one percent and 26%, respectively, did have one of these cytogenetic abnormalities. (For the remaining patients, cytogenetic risk data were missing.)

PBSC mobilization and response

The median number of PBSCs collected was 8.6 x 10⁶/kg in the KCD arm and 6.3 x 10⁶/kg in the KRD arm. Plerixafor was required in 6% of patients in the KCD arm and 28% of patients in the KRD arm (P<0.001).

Ninety-two percent of patients in the KCD arm and 96% in the KRD arm had a partial response or better. Sixty-one percent and 74%, respectively, had a very good partial response (P=0.01). Six percent and 15%, respectively, had a complete response.

Safety

Grade 3/4 hematologic AEs and serious AEs (in the KRD and KCD arms, respectively) were thrombocytopenia (2% and 1%), neutropenia (6% and 5%), and anemia (2% and 3%). Seven percent of KRD patients and 6% of KCD patients had at least 1 grade 3/4 or serious hematologic AE.

Grade 3/4 non-hematologic AEs and serious AEs (in the KRD and KCD arms, respectively) included dermatologic events (8% and 1%, P<0.001), renal events (1% and 2%), fever (4% and 1%), infections (5% and 3%), gastrointestinal AEs (2% and 1%), hepatic events (8% and 1%, P<0.001), venous thromboembolism (1% and 0%), hypertension (3% and 2%), and cardiac events (1% and 2%).

Thirty-two percent of KRD patients and 16% of KCD patients had at least 1 grade 3/4 or serious non-hematologic AE (P<0.001).

Four percent of patients in the KRD arm and 2% in the KCD arm discontinued treatment due to AEs. Fifteen percent and 6%, respectively, reduced the dose of at least 1 drug (P=0.005).

One percent of patients in the KRD arm and 2% in the KCD arm died from AEs. In the KCD arm, 1 patient had a sudden death, and 1 died of pneumonia. In the KRD arm, there was 1 sudden death in a patient with sepsis, 1 patient died of infection, and 1 died of cardiac arrest (this patient previously discontinued treatment due to renal failure).

Micrograph showing MM

MADRID—New research suggests one triplet regimen may be more active but also more toxic than another in patients with newly diagnosed multiple myeloma (MM).

In the FORTE trial, the combination of carfilzomib, lenalidomide, and dexamethasone (KRD) produced higher response rates than carfilzomib, cyclophosphamide, and dexamethasone (KCD).

However, treatment with KRD also produced significantly more grade 3/4 non-hematologic adverse events (AEs) and serious AEs than the KCD regimen.

Francesca Gay, MD, PhD, of University of Torino in Italy, presented these results, from a planned interim analysis of FORTE, at the 22nd Congress of the European Hematology Association (EHA) as abstract S410.

The trial enrolled 477 MM patients younger than 65 years of age.

The patients were randomized to receive:

• Four 28-day KCD cycles (n=154)

  Carfilzomib at 20 mg/m² (for cycles 1 and 2) or 36 mg/m² (for subsequent cycles) on days 1, 2, 8, 9, 15, and 16

  Cyclophosphamide at 300 mg/m² on days 1, 8, and 15

  Dexamethasone at 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23

• Four 28-day KRD cycles (n=309)

  Carfilzomib and dexamethasone as above

  Lenalidomide at 25 mg on days 1-21

After the fourth induction cycle, all patients received cyclophosphamide at 2 g/m², followed by peripheral blood stem cell (PBSC) collection for autologous stem cell transplant.

Patient characteristics

The median age was 57 (range, 52-62) in the KCD arm and the KRD arm (range, 51-62). In both arms, 55% of patients were male.

Roughly half of patients in both arms had an ISS stage of I (52% in the KCD arm and 51% in the KRD arm), 31% of patients in both arms were stage II, and 17% were stage III.

Fifty-eight percent of patients in the KCD arm and 59% in the KRD arm did not have t(4;14), t(14;16), or del17. Thirty-one percent and 26%, respectively, did have one of these cytogenetic abnormalities. (For the remaining patients, cytogenetic risk data were missing.)

PBSC mobilization and response

The median number of PBSCs collected was 8.6 x 10⁶/kg in the KCD arm and 6.3 x 10⁶/kg in the KRD arm. Plerixafor was required in 6% of patients in the KCD arm and 28% of patients in the KRD arm (P<0.001).

Ninety-two percent of patients in the KCD arm and 96% in the KRD arm had a partial response or better. Sixty-one percent and 74%, respectively, had a very good partial response (P=0.01). Six percent and 15%, respectively, had a complete response.

Safety

Grade 3/4 hematologic AEs and serious AEs (in the KRD and KCD arms, respectively) were thrombocytopenia (2% and 1%), neutropenia (6% and 5%), and anemia (2% and 3%). Seven percent of KRD patients and 6% of KCD patients had at least 1 grade 3/4 or serious hematologic AE.

Grade 3/4 non-hematologic AEs and serious AEs (in the KRD and KCD arms, respectively) included dermatologic events (8% and 1%, P<0.001), renal events (1% and 2%), fever (4% and 1%), infections (5% and 3%), gastrointestinal AEs (2% and 1%), hepatic events (8% and 1%, P<0.001), venous thromboembolism (1% and 0%), hypertension (3% and 2%), and cardiac events (1% and 2%).

Thirty-two percent of KRD patients and 16% of KCD patients had at least 1 grade 3/4 or serious non-hematologic AE (P<0.001).

Four percent of patients in the KRD arm and 2% in the KCD arm discontinued treatment due to AEs. Fifteen percent and 6%, respectively, reduced the dose of at least 1 drug (P=0.005).

One percent of patients in the KRD arm and 2% in the KCD arm died from AEs. In the KCD arm, 1 patient had a sudden death, and 1 died of pneumonia. In the KRD arm, there was 1 sudden death in a patient with sepsis, 1 patient died of infection, and 1 died of cardiac arrest (this patient previously discontinued treatment due to renal failure).

Image courtesy of AFIP

MADRID—Long-term maintenance with ropeginterferon alfa-2b is feasible, effective, and well-tolerated in patients with polycythemia vera (PV), according to researchers.

In the ongoing phase 1/2 PEGINVERA study, patients have received ropeginterferon alfa-2b for a median of 4 years.

After the first 2 years, patients switched from bi-weekly dosing to receiving ropeginterferon alfa-2b once every 4 weeks.

None of the patients discontinued treatment after the switch, and many were able to maintain their best response.

Most adverse events (AEs) were mild, although there were several severe treatment-related AEs.

These results were presented in a poster (abstract P707) at the 22nd Congress of the European Hematology Association (EHA). The research was funded by AOP Orphan Pharmaceuticals AG.

The trial enrolled 51 patients, but the researchers reported results in the 29 patients who had completed 2 years of treatment and switched from bi-weekly dosing to receiving treatment once every 4 weeks.

All 29 patients remained on the 4-week schedule with a median observation period of roughly 2 years. The median monthly dose was 308 μg before the switch and 165 μg after.

At study entry, the patients’ median age was 58 (range, 40-80), and 76% were male. Their median spleen length was 12.8 cm (range, 8.0-22.0), and 34% of patients had prior treatment with hydroxyurea.

Patients’ median hematocrit was 45.40% (range, 36.9-53.8), their median platelet count was 431 G/L (range, 225-1016), their median leukocyte count was 11.1 G/L (range, 4.7-30.9), and their median JAKV617F allelic burden was 78% (range, 2-91.5).

Results

More than 80% of patients achieved a hematologic response, with more than 50% achieving a complete hematologic response. The same percentage of patients maintained their best hematologic response before and 6 months after switching to the 4-week schedule—51.7%.

More than 80% of patients achieved a molecular response, with nearly 20% achieving a complete molecular response. The percentage of patients maintaining their best molecular response was 62.1% before switching to the 4-week schedule and 58.6% 6 months after the switch.

The researchers said changes in hematocrit, platelet count, leukocyte count, and spleen size after the switch were “minimal and without clinical relevance.”

The median hematocrit changed from 42.3% to 42.6%, the median platelet count changed from 201.0 x 10⁹/L to 211.9 x 10⁹/L, the median leukocyte count changed from 5.0 x 10⁹/L to 5.6 x 10⁹/L, and the median spleen size changed from 12.8 cm to 12.4 cm.

The need for phlebotomy did not change, with 24.1% of patients requiring phlebotomy both before and 6 months after the switch.

The researchers also noted that ropeginterferon alfa-2b decreased mutant JAK2 allele burden in all of the patients over time, with the strongest effect observed in the second year of treatment.

After 2 years, most patients had a burden below 10%, and this was not affected by the change in dosing.

There were no cases of progression to myelofibrosis or leukemic transformation.

Seventy-one percent of AEs were mild, and 40.4% were considered likely related to ropeginterferon alfa-2b. The most frequent treatment-related AEs were arthralgia (29.4%) and fatigue (21.6%).

There were 34 severe AEs, 11 of which were related to ropeginterferon alfa-2b.

Image courtesy of AFIP

MADRID—Long-term maintenance with ropeginterferon alfa-2b is feasible, effective, and well-tolerated in patients with polycythemia vera (PV), according to researchers.

In the ongoing phase 1/2 PEGINVERA study, patients have received ropeginterferon alfa-2b for a median of 4 years.

After the first 2 years, patients switched from bi-weekly dosing to receiving ropeginterferon alfa-2b once every 4 weeks.

None of the patients discontinued treatment after the switch, and many were able to maintain their best response.

Most adverse events (AEs) were mild, although there were several severe treatment-related AEs.

These results were presented in a poster (abstract P707) at the 22nd Congress of the European Hematology Association (EHA). The research was funded by AOP Orphan Pharmaceuticals AG.

The trial enrolled 51 patients, but the researchers reported results in the 29 patients who had completed 2 years of treatment and switched from bi-weekly dosing to receiving treatment once every 4 weeks.

All 29 patients remained on the 4-week schedule with a median observation period of roughly 2 years. The median monthly dose was 308 μg before the switch and 165 μg after.

At study entry, the patients’ median age was 58 (range, 40-80), and 76% were male. Their median spleen length was 12.8 cm (range, 8.0-22.0), and 34% of patients had prior treatment with hydroxyurea.

Patients’ median hematocrit was 45.40% (range, 36.9-53.8), their median platelet count was 431 G/L (range, 225-1016), their median leukocyte count was 11.1 G/L (range, 4.7-30.9), and their median JAKV617F allelic burden was 78% (range, 2-91.5).

Results

More than 80% of patients achieved a hematologic response, with more than 50% achieving a complete hematologic response. The same percentage of patients maintained their best hematologic response before and 6 months after switching to the 4-week schedule—51.7%.

More than 80% of patients achieved a molecular response, with nearly 20% achieving a complete molecular response. The percentage of patients maintaining their best molecular response was 62.1% before switching to the 4-week schedule and 58.6% 6 months after the switch.

The researchers said changes in hematocrit, platelet count, leukocyte count, and spleen size after the switch were “minimal and without clinical relevance.”

The median hematocrit changed from 42.3% to 42.6%, the median platelet count changed from 201.0 x 10⁹/L to 211.9 x 10⁹/L, the median leukocyte count changed from 5.0 x 10⁹/L to 5.6 x 10⁹/L, and the median spleen size changed from 12.8 cm to 12.4 cm.

The need for phlebotomy did not change, with 24.1% of patients requiring phlebotomy both before and 6 months after the switch.

The researchers also noted that ropeginterferon alfa-2b decreased mutant JAK2 allele burden in all of the patients over time, with the strongest effect observed in the second year of treatment.

After 2 years, most patients had a burden below 10%, and this was not affected by the change in dosing.

There were no cases of progression to myelofibrosis or leukemic transformation.

Seventy-one percent of AEs were mild, and 40.4% were considered likely related to ropeginterferon alfa-2b. The most frequent treatment-related AEs were arthralgia (29.4%) and fatigue (21.6%).

There were 34 severe AEs, 11 of which were related to ropeginterferon alfa-2b.

Image courtesy of AFIP

MADRID—Long-term maintenance with ropeginterferon alfa-2b is feasible, effective, and well-tolerated in patients with polycythemia vera (PV), according to researchers.

In the ongoing phase 1/2 PEGINVERA study, patients have received ropeginterferon alfa-2b for a median of 4 years.

After the first 2 years, patients switched from bi-weekly dosing to receiving ropeginterferon alfa-2b once every 4 weeks.

None of the patients discontinued treatment after the switch, and many were able to maintain their best response.

Most adverse events (AEs) were mild, although there were several severe treatment-related AEs.

These results were presented in a poster (abstract P707) at the 22nd Congress of the European Hematology Association (EHA). The research was funded by AOP Orphan Pharmaceuticals AG.

The trial enrolled 51 patients, but the researchers reported results in the 29 patients who had completed 2 years of treatment and switched from bi-weekly dosing to receiving treatment once every 4 weeks.

All 29 patients remained on the 4-week schedule with a median observation period of roughly 2 years. The median monthly dose was 308 μg before the switch and 165 μg after.

At study entry, the patients’ median age was 58 (range, 40-80), and 76% were male. Their median spleen length was 12.8 cm (range, 8.0-22.0), and 34% of patients had prior treatment with hydroxyurea.

Patients’ median hematocrit was 45.40% (range, 36.9-53.8), their median platelet count was 431 G/L (range, 225-1016), their median leukocyte count was 11.1 G/L (range, 4.7-30.9), and their median JAKV617F allelic burden was 78% (range, 2-91.5).

Results

More than 80% of patients achieved a hematologic response, with more than 50% achieving a complete hematologic response. The same percentage of patients maintained their best hematologic response before and 6 months after switching to the 4-week schedule—51.7%.

More than 80% of patients achieved a molecular response, with nearly 20% achieving a complete molecular response. The percentage of patients maintaining their best molecular response was 62.1% before switching to the 4-week schedule and 58.6% 6 months after the switch.

The researchers said changes in hematocrit, platelet count, leukocyte count, and spleen size after the switch were “minimal and without clinical relevance.”

The median hematocrit changed from 42.3% to 42.6%, the median platelet count changed from 201.0 x 10⁹/L to 211.9 x 10⁹/L, the median leukocyte count changed from 5.0 x 10⁹/L to 5.6 x 10⁹/L, and the median spleen size changed from 12.8 cm to 12.4 cm.

The need for phlebotomy did not change, with 24.1% of patients requiring phlebotomy both before and 6 months after the switch.

The researchers also noted that ropeginterferon alfa-2b decreased mutant JAK2 allele burden in all of the patients over time, with the strongest effect observed in the second year of treatment.

After 2 years, most patients had a burden below 10%, and this was not affected by the change in dosing.

There were no cases of progression to myelofibrosis or leukemic transformation.

Seventy-one percent of AEs were mild, and 40.4% were considered likely related to ropeginterferon alfa-2b. The most frequent treatment-related AEs were arthralgia (29.4%) and fatigue (21.6%).

There were 34 severe AEs, 11 of which were related to ropeginterferon alfa-2b.

Andrew Wei, MBBS, PhD

MADRID—The combination of venetoclax and low-dose cytarabine (VEN+LDAC) appears to be a feasible treatment option for elderly patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.

In a phase 1/2 study of such patients, VEN+LDAC was considered well-tolerated, conferring moderate myelosuppression and largely low-grade non-hematologic toxicities.

In addition, the combination produced “rapid and durable” responses, and early death rates were low, according to Andrew H. Wei, MBBS, PhD, of Monash University in Melbourne, Victoria, Australia.

However, nearly three-quarters of patients ultimately discontinued the treatment, many due to disease progression.

Dr Wei presented these results at the 22nd Congress of the European Hematology Association (EHA) as abstract S473. AbbVie and Genentech, the companies developing and marketing venetoclax, provided financial support for this study.

“Expression of pro-survival proteins is an established mechanism of chemoresistance in diverse cancers,” Dr Wei noted. “BCL-2 is 1 of 5 pro-survival molecules which functions to sequester pro-apoptotic molecules and tip the balance in favor of cell survival.”

“Venetoclax is a potent and specific inhibitor of BCL-2 which releases these pro-apoptotic molecules, tipping the balance in favor of cell death. Cytotoxic drugs are well-known to increase the burden of BH3-only proteins, and so it was surmised that the combination of chemotherapy, such as cytarabine, with venetoclax could augment the clinical response.”

Patients

Dr Wei presented data on 61 AML patients treated with VEN+LDAC. He noted that this was a poor-risk population, with nearly half of patients over the age of 75 at baseline.

The patients’ median age was 74 (range, 66-87), and 64% were male. Nearly half of patients had an ECOG performance status of 1 (49%), 30% had a status of 0, and 21% had a status of 2.

Forty-four percent of patients had secondary AML, and 28% had prior treatment with a hypomethylating agent (HMA). Sixty-one percent of patients had intermediate-risk cytogenetics, and 31% had poor-risk cytogenetics.

Treatment

The patients received oral venetoclax at 600 mg daily on days 1 to 28 and subcutaneous cytarabine at 20 mg/m² daily on days 1 to 10 of each 28-day cycle.

In the first cycle, the dose of venetoclax was ramped up gradually—no dose on day 1, 50 mg on day 2, 100 mg on day 3, 200 mg on day 4, 400 mg on day 5, and 600 mg thereafter.

Patients received prophylaxis for tumor lysis syndrome prior to starting cycle 1, and they were hospitalized to enable observation.

The median time on study treatment was 6 months (range, <1 to 19 months). Seventy-two percent of patients discontinued treatment.

Reasons for discontinuation included:

• Progressive disease without death—26%
• Progressive disease with death—10%
• Adverse event (AE) related to progression—10%
• AE not related to progression—8%
• Withdrawn consent—8%
• Other reasons—18%.

Safety

The most common AEs of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).

Grade 3/4 hematologic AEs (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), and anemia (28%).

Grade 3/4 non-hematologic AEs (occurring in at least 10% of patients) included hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%).

Response and survival

The overall response rate was 65%, with 25% of patients achieving a complete response (CR), 38% having a CR with incomplete blood count recovery (CRi), and 2% experiencing a partial response.

Dr Wei noted that VEN+LDAC was active across subgroups.

The CR/CRi rate was 76% among patients with intermediate-risk cytogenetics and 47% among patients with poor-risk cytogenetics.

The CR/CRi rate was 70% among patients older than 75, 52% among patients with secondary AML, 66% among patients with no prior HMA exposure, and 53% in patients with prior HMA exposure.

“Although responses were slightly lower in patients with poor cytogenetic risk, prior HMA exposure, and secondary AML . . ., these responses are far in excess of what we would expect with [LDAC] alone,” Dr Wei said.

“Furthermore, the median time to response was very rapid, and this is extremely important to get patients into remission and avoid the medium-term consequences of active AML.”

The median time to response was 1 month (range, <1 to 9 months).

The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.

Based on these results, AbbVie has initiated a phase 3 trial comparing VEN+LDAC to LDAC alone in elderly patients with untreated AML who are ineligible for intensive chemotherapy.

Andrew Wei, MBBS, PhD

MADRID—The combination of venetoclax and low-dose cytarabine (VEN+LDAC) appears to be a feasible treatment option for elderly patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.

In a phase 1/2 study of such patients, VEN+LDAC was considered well-tolerated, conferring moderate myelosuppression and largely low-grade non-hematologic toxicities.

In addition, the combination produced “rapid and durable” responses, and early death rates were low, according to Andrew H. Wei, MBBS, PhD, of Monash University in Melbourne, Victoria, Australia.

However, nearly three-quarters of patients ultimately discontinued the treatment, many due to disease progression.

Dr Wei presented these results at the 22nd Congress of the European Hematology Association (EHA) as abstract S473. AbbVie and Genentech, the companies developing and marketing venetoclax, provided financial support for this study.

“Expression of pro-survival proteins is an established mechanism of chemoresistance in diverse cancers,” Dr Wei noted. “BCL-2 is 1 of 5 pro-survival molecules which functions to sequester pro-apoptotic molecules and tip the balance in favor of cell survival.”

“Venetoclax is a potent and specific inhibitor of BCL-2 which releases these pro-apoptotic molecules, tipping the balance in favor of cell death. Cytotoxic drugs are well-known to increase the burden of BH3-only proteins, and so it was surmised that the combination of chemotherapy, such as cytarabine, with venetoclax could augment the clinical response.”

Patients

Dr Wei presented data on 61 AML patients treated with VEN+LDAC. He noted that this was a poor-risk population, with nearly half of patients over the age of 75 at baseline.

The patients’ median age was 74 (range, 66-87), and 64% were male. Nearly half of patients had an ECOG performance status of 1 (49%), 30% had a status of 0, and 21% had a status of 2.

Forty-four percent of patients had secondary AML, and 28% had prior treatment with a hypomethylating agent (HMA). Sixty-one percent of patients had intermediate-risk cytogenetics, and 31% had poor-risk cytogenetics.

Treatment

The patients received oral venetoclax at 600 mg daily on days 1 to 28 and subcutaneous cytarabine at 20 mg/m² daily on days 1 to 10 of each 28-day cycle.

In the first cycle, the dose of venetoclax was ramped up gradually—no dose on day 1, 50 mg on day 2, 100 mg on day 3, 200 mg on day 4, 400 mg on day 5, and 600 mg thereafter.

Patients received prophylaxis for tumor lysis syndrome prior to starting cycle 1, and they were hospitalized to enable observation.

The median time on study treatment was 6 months (range, <1 to 19 months). Seventy-two percent of patients discontinued treatment.

Reasons for discontinuation included:

• Progressive disease without death—26%
• Progressive disease with death—10%
• Adverse event (AE) related to progression—10%
• AE not related to progression—8%
• Withdrawn consent—8%
• Other reasons—18%.

Safety

The most common AEs of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).

Grade 3/4 hematologic AEs (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), and anemia (28%).

Grade 3/4 non-hematologic AEs (occurring in at least 10% of patients) included hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%).

Response and survival

The overall response rate was 65%, with 25% of patients achieving a complete response (CR), 38% having a CR with incomplete blood count recovery (CRi), and 2% experiencing a partial response.

Dr Wei noted that VEN+LDAC was active across subgroups.

The CR/CRi rate was 76% among patients with intermediate-risk cytogenetics and 47% among patients with poor-risk cytogenetics.

The CR/CRi rate was 70% among patients older than 75, 52% among patients with secondary AML, 66% among patients with no prior HMA exposure, and 53% in patients with prior HMA exposure.

“Although responses were slightly lower in patients with poor cytogenetic risk, prior HMA exposure, and secondary AML . . ., these responses are far in excess of what we would expect with [LDAC] alone,” Dr Wei said.

“Furthermore, the median time to response was very rapid, and this is extremely important to get patients into remission and avoid the medium-term consequences of active AML.”

The median time to response was 1 month (range, <1 to 9 months).

The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.

Based on these results, AbbVie has initiated a phase 3 trial comparing VEN+LDAC to LDAC alone in elderly patients with untreated AML who are ineligible for intensive chemotherapy.

Andrew Wei, MBBS, PhD

MADRID—The combination of venetoclax and low-dose cytarabine (VEN+LDAC) appears to be a feasible treatment option for elderly patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.

In a phase 1/2 study of such patients, VEN+LDAC was considered well-tolerated, conferring moderate myelosuppression and largely low-grade non-hematologic toxicities.

In addition, the combination produced “rapid and durable” responses, and early death rates were low, according to Andrew H. Wei, MBBS, PhD, of Monash University in Melbourne, Victoria, Australia.

However, nearly three-quarters of patients ultimately discontinued the treatment, many due to disease progression.

Dr Wei presented these results at the 22nd Congress of the European Hematology Association (EHA) as abstract S473. AbbVie and Genentech, the companies developing and marketing venetoclax, provided financial support for this study.

“Expression of pro-survival proteins is an established mechanism of chemoresistance in diverse cancers,” Dr Wei noted. “BCL-2 is 1 of 5 pro-survival molecules which functions to sequester pro-apoptotic molecules and tip the balance in favor of cell survival.”

“Venetoclax is a potent and specific inhibitor of BCL-2 which releases these pro-apoptotic molecules, tipping the balance in favor of cell death. Cytotoxic drugs are well-known to increase the burden of BH3-only proteins, and so it was surmised that the combination of chemotherapy, such as cytarabine, with venetoclax could augment the clinical response.”

Patients

Dr Wei presented data on 61 AML patients treated with VEN+LDAC. He noted that this was a poor-risk population, with nearly half of patients over the age of 75 at baseline.

The patients’ median age was 74 (range, 66-87), and 64% were male. Nearly half of patients had an ECOG performance status of 1 (49%), 30% had a status of 0, and 21% had a status of 2.

Forty-four percent of patients had secondary AML, and 28% had prior treatment with a hypomethylating agent (HMA). Sixty-one percent of patients had intermediate-risk cytogenetics, and 31% had poor-risk cytogenetics.

Treatment

The patients received oral venetoclax at 600 mg daily on days 1 to 28 and subcutaneous cytarabine at 20 mg/m² daily on days 1 to 10 of each 28-day cycle.

In the first cycle, the dose of venetoclax was ramped up gradually—no dose on day 1, 50 mg on day 2, 100 mg on day 3, 200 mg on day 4, 400 mg on day 5, and 600 mg thereafter.

Patients received prophylaxis for tumor lysis syndrome prior to starting cycle 1, and they were hospitalized to enable observation.

The median time on study treatment was 6 months (range, <1 to 19 months). Seventy-two percent of patients discontinued treatment.

Reasons for discontinuation included:

• Progressive disease without death—26%
• Progressive disease with death—10%
• Adverse event (AE) related to progression—10%
• AE not related to progression—8%
• Withdrawn consent—8%
• Other reasons—18%.

Safety

The most common AEs of any grade (occurring in at least 30% of patients) were nausea (74%), hypokalemia (46%), diarrhea (46%), fatigue (44%), decreased appetite (41%), constipation (34%), hypomagnesemia (34%), vomiting (31%), thrombocytopenia (44%), febrile neutropenia (38%), and neutropenia (33%).

Grade 3/4 hematologic AEs (occurring in at least 10% of patients) included thrombocytopenia (44%), febrile neutropenia (36%), neutropenia (33%), and anemia (28%).

Grade 3/4 non-hematologic AEs (occurring in at least 10% of patients) included hypokalemia (16%), hypophosphatemia (13%), and hypertension (12%).

Response and survival

The overall response rate was 65%, with 25% of patients achieving a complete response (CR), 38% having a CR with incomplete blood count recovery (CRi), and 2% experiencing a partial response.

Dr Wei noted that VEN+LDAC was active across subgroups.

The CR/CRi rate was 76% among patients with intermediate-risk cytogenetics and 47% among patients with poor-risk cytogenetics.

The CR/CRi rate was 70% among patients older than 75, 52% among patients with secondary AML, 66% among patients with no prior HMA exposure, and 53% in patients with prior HMA exposure.

“Although responses were slightly lower in patients with poor cytogenetic risk, prior HMA exposure, and secondary AML . . ., these responses are far in excess of what we would expect with [LDAC] alone,” Dr Wei said.

“Furthermore, the median time to response was very rapid, and this is extremely important to get patients into remission and avoid the medium-term consequences of active AML.”

The median time to response was 1 month (range, <1 to 9 months).

The 30-day death rate was 3%, the 60-day death rate was 15%, and the median overall survival was approximately 12 months.

Based on these results, AbbVie has initiated a phase 3 trial comparing VEN+LDAC to LDAC alone in elderly patients with untreated AML who are ineligible for intensive chemotherapy.

MADRID – A combination of the BCL-2 inhibitor venetoclax with a hypomethylating agent may produce high overall response rates among older patients with newly diagnosed acute myeloid leukemia (AML), early data showed.

Among 100 patients age 65 years and older with previously untreated AML, the combination of venetoclax with either decitabine or azacitidine was associated with a 69% overall responses rate, reported Keith W. Pratz, MD, of Johns Hopkins University in Baltimore.

• Decitabine plus venetoclax 400 mg: 76% (44% CR, 32% CRi).
• Decitabine plus venetoclax 800 mg: 68% (36% CR, 32% CRi).
• Azacitadine plus venetoclax 400 mg: 72% (28% CR, 44% CRi).
• Azacitadine plus venetoclax 800 mg: 56%: (28% CR, 28% CRi, PR 1% [numbers rounded up]).

The combined CR/CRi rate was 60% among patients with poor-risk cytogenetics and 78% among patients with intermediate-risk disease. In addition, the combination was effective among patients with both primary de novo AML (68%) and secondary AML (related to myelodysplasia or myeloproliferative neoplasms or previous therapy; 73%).

Overall survival after a median of 9 months since the first dose of the study drug was estimated to be 79% at 6 months and 70% at 12 months, with the median not reached.

Treatment-related adverse events were similar between the decitabine- and azacitidine-containing arms at the given dose of venetoclax. Grade 3 or 4 treatment-related adverse events included thrombocytopenia in 56% of patients on the 400-mg dose of venetoclax and in 32% of those on the 800-mg dose. Grade 3/4 febrile neutropenia occurred in 48% and 30%, respectively, and neutropenia in 40% and 32%.

A phase 3 study of venetoclax at the 400-mg dose with azacitidine has been initiated. NCT02993523 is currently enrolling patients, Dr. Pratz said.

The study was supported by Abbvie and Genentech. Dr. Pratz disclosed research funding from Abbvie and other companies.

MADRID – A combination of the BCL-2 inhibitor venetoclax with a hypomethylating agent may produce high overall response rates among older patients with newly diagnosed acute myeloid leukemia (AML), early data showed.

Among 100 patients age 65 years and older with previously untreated AML, the combination of venetoclax with either decitabine or azacitidine was associated with a 69% overall responses rate, reported Keith W. Pratz, MD, of Johns Hopkins University in Baltimore.

• Decitabine plus venetoclax 400 mg: 76% (44% CR, 32% CRi).
• Decitabine plus venetoclax 800 mg: 68% (36% CR, 32% CRi).
• Azacitadine plus venetoclax 400 mg: 72% (28% CR, 44% CRi).
• Azacitadine plus venetoclax 800 mg: 56%: (28% CR, 28% CRi, PR 1% [numbers rounded up]).

The combined CR/CRi rate was 60% among patients with poor-risk cytogenetics and 78% among patients with intermediate-risk disease. In addition, the combination was effective among patients with both primary de novo AML (68%) and secondary AML (related to myelodysplasia or myeloproliferative neoplasms or previous therapy; 73%).

Overall survival after a median of 9 months since the first dose of the study drug was estimated to be 79% at 6 months and 70% at 12 months, with the median not reached.

Treatment-related adverse events were similar between the decitabine- and azacitidine-containing arms at the given dose of venetoclax. Grade 3 or 4 treatment-related adverse events included thrombocytopenia in 56% of patients on the 400-mg dose of venetoclax and in 32% of those on the 800-mg dose. Grade 3/4 febrile neutropenia occurred in 48% and 30%, respectively, and neutropenia in 40% and 32%.

A phase 3 study of venetoclax at the 400-mg dose with azacitidine has been initiated. NCT02993523 is currently enrolling patients, Dr. Pratz said.

The study was supported by Abbvie and Genentech. Dr. Pratz disclosed research funding from Abbvie and other companies.

MADRID – A combination of the BCL-2 inhibitor venetoclax with a hypomethylating agent may produce high overall response rates among older patients with newly diagnosed acute myeloid leukemia (AML), early data showed.

Among 100 patients age 65 years and older with previously untreated AML, the combination of venetoclax with either decitabine or azacitidine was associated with a 69% overall responses rate, reported Keith W. Pratz, MD, of Johns Hopkins University in Baltimore.

• Decitabine plus venetoclax 400 mg: 76% (44% CR, 32% CRi).
• Decitabine plus venetoclax 800 mg: 68% (36% CR, 32% CRi).
• Azacitadine plus venetoclax 400 mg: 72% (28% CR, 44% CRi).
• Azacitadine plus venetoclax 800 mg: 56%: (28% CR, 28% CRi, PR 1% [numbers rounded up]).

The combined CR/CRi rate was 60% among patients with poor-risk cytogenetics and 78% among patients with intermediate-risk disease. In addition, the combination was effective among patients with both primary de novo AML (68%) and secondary AML (related to myelodysplasia or myeloproliferative neoplasms or previous therapy; 73%).

Overall survival after a median of 9 months since the first dose of the study drug was estimated to be 79% at 6 months and 70% at 12 months, with the median not reached.

Treatment-related adverse events were similar between the decitabine- and azacitidine-containing arms at the given dose of venetoclax. Grade 3 or 4 treatment-related adverse events included thrombocytopenia in 56% of patients on the 400-mg dose of venetoclax and in 32% of those on the 800-mg dose. Grade 3/4 febrile neutropenia occurred in 48% and 30%, respectively, and neutropenia in 40% and 32%.

A phase 3 study of venetoclax at the 400-mg dose with azacitidine has been initiated. NCT02993523 is currently enrolling patients, Dr. Pratz said.

The study was supported by Abbvie and Genentech. Dr. Pratz disclosed research funding from Abbvie and other companies.

Gilles Salles, MD, PhD

The chimeric antigen receptor (CAR) T-cell therapy CTL019 produced a high response rate in a phase 2 trial of adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to researchers.

An interim analysis of the JULIET trial revealed a 3-month overall response rate (ORR) of 45%.

Thirty-seven percent of patients had a complete response (CR), and all of the patients who were in CR at 3 months were still in CR at the data cutoff point.

This confirms the high response rates and durable responses observed in a previous single-center trial*, said JULIET investigator Gilles Salles, MD, PhD, of Hospices Civils de Lyon in Lyon, France.

Dr Salles presented results from JULIET at the 22nd Congress of the European Hematology Association (EHA) in Madrid, Spain (abstract LB2604).

The results were also presented at the 14th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland (abstract 007).

The study was sponsored by Novartis.

Patients

JULIET enrolled 141 patients age 18 and older with relapsed/refractory DLBCL.

Forty-three patients discontinued the study before receiving CTL019—28 due to progressive disease (including 16 deaths), 9 due to an inability to manufacture CTL019, 2 due to adverse events, 1 due to investigator decision, 1 due to study withdrawal, and 1 due to protocol deviation.

Eighty-five patients were infused. The remaining 13 patients were pending infusion at the data cutoff—December 20, 2016.

The median age of the 85 infused patients was 56 (range, 24-75). Ninety-six percent of patients had DLBCL not otherwise specified. Fifty-one percent had germinal center B-cell type DLBCL.

Fifty-four percent of patients had an ECOG performance status of 0, and 46% had a status of 1. Fifty-three percent of patients had stage IV disease, and 8% had bone marrow involvement.

Forty percent of patients had 2 prior lines of antineoplastic therapy, 29% had 3, and 31% had 4 to 7 prior lines.

Forty-one percent of patients were refractory to their last therapy, and 59% had relapsed after their last therapy. Fifty-one percent of patients had prior autologous stem cell transplant.

Treatment

Seventy-six patients (89%) received bridging chemotherapy to prevent disease progression during CTL019 manufacturing. This treatment was completed 2 to 14 days prior to CTL019 infusion.

The median CTL019 cell dose was 3.1 x 10⁸ (range, 0.1-6.0 x 10⁸).

Response

Fifty-one patients were evaluated for response. The median time from infusion to data cutoff was 3.7 months.

The best ORR was 59%, with a CR rate of 43% and a partial response rate of 16%. Twelve percent of patients had stable disease, and 24% progressed.

At 3 months, the ORR was 45%. The CR rate was 37%, and the partial response rate was 8%.

“All patients in CR at 3 months remained in CR at follow-up, and the median duration of response was not reached,” Dr Salles noted.

None of the responders went on to receive a transplant.

Safety

All 85 patients were evaluated for safety. Adverse events of special interest, occurring within 8 weeks of CTL019 infusion, were:

• Cytokine release syndrome—57% all grades, 17% grade 3, 9% grade 4
• Infections—27% all grades, 12% grade 3, 1% grade 4
• Cytopenias not resolved by day 28—26% all grades, 13% grade 3, 8% grade 4
• Neurologic events—21% all grades, 9% grade 3, 4% grade 4
• Febrile neutropenia—14% all grades, 13% grade 3, 1% grade 4
• Tumor lysis syndrome—1% grade 3.

“Adverse events were reversible and effectively managed at the different centers by appropriately trained study personnel,” Dr Salles noted. “There were no CTL019-related deaths and no cerebral edema.”

*SJ Schuster et al, 2016 ASH Annual Meeting, abstract 3026

Gilles Salles, MD, PhD

The chimeric antigen receptor (CAR) T-cell therapy CTL019 produced a high response rate in a phase 2 trial of adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to researchers.

An interim analysis of the JULIET trial revealed a 3-month overall response rate (ORR) of 45%.

Thirty-seven percent of patients had a complete response (CR), and all of the patients who were in CR at 3 months were still in CR at the data cutoff point.

This confirms the high response rates and durable responses observed in a previous single-center trial*, said JULIET investigator Gilles Salles, MD, PhD, of Hospices Civils de Lyon in Lyon, France.

Dr Salles presented results from JULIET at the 22nd Congress of the European Hematology Association (EHA) in Madrid, Spain (abstract LB2604).

The results were also presented at the 14th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland (abstract 007).

The study was sponsored by Novartis.

Patients

JULIET enrolled 141 patients age 18 and older with relapsed/refractory DLBCL.

Forty-three patients discontinued the study before receiving CTL019—28 due to progressive disease (including 16 deaths), 9 due to an inability to manufacture CTL019, 2 due to adverse events, 1 due to investigator decision, 1 due to study withdrawal, and 1 due to protocol deviation.

Eighty-five patients were infused. The remaining 13 patients were pending infusion at the data cutoff—December 20, 2016.

The median age of the 85 infused patients was 56 (range, 24-75). Ninety-six percent of patients had DLBCL not otherwise specified. Fifty-one percent had germinal center B-cell type DLBCL.

Fifty-four percent of patients had an ECOG performance status of 0, and 46% had a status of 1. Fifty-three percent of patients had stage IV disease, and 8% had bone marrow involvement.

Forty percent of patients had 2 prior lines of antineoplastic therapy, 29% had 3, and 31% had 4 to 7 prior lines.

Forty-one percent of patients were refractory to their last therapy, and 59% had relapsed after their last therapy. Fifty-one percent of patients had prior autologous stem cell transplant.

Treatment

Seventy-six patients (89%) received bridging chemotherapy to prevent disease progression during CTL019 manufacturing. This treatment was completed 2 to 14 days prior to CTL019 infusion.

The median CTL019 cell dose was 3.1 x 10⁸ (range, 0.1-6.0 x 10⁸).

Response

Fifty-one patients were evaluated for response. The median time from infusion to data cutoff was 3.7 months.

The best ORR was 59%, with a CR rate of 43% and a partial response rate of 16%. Twelve percent of patients had stable disease, and 24% progressed.

At 3 months, the ORR was 45%. The CR rate was 37%, and the partial response rate was 8%.

“All patients in CR at 3 months remained in CR at follow-up, and the median duration of response was not reached,” Dr Salles noted.

None of the responders went on to receive a transplant.

Safety

All 85 patients were evaluated for safety. Adverse events of special interest, occurring within 8 weeks of CTL019 infusion, were:

• Cytokine release syndrome—57% all grades, 17% grade 3, 9% grade 4
• Infections—27% all grades, 12% grade 3, 1% grade 4
• Cytopenias not resolved by day 28—26% all grades, 13% grade 3, 8% grade 4
• Neurologic events—21% all grades, 9% grade 3, 4% grade 4
• Febrile neutropenia—14% all grades, 13% grade 3, 1% grade 4
• Tumor lysis syndrome—1% grade 3.

“Adverse events were reversible and effectively managed at the different centers by appropriately trained study personnel,” Dr Salles noted. “There were no CTL019-related deaths and no cerebral edema.”

*SJ Schuster et al, 2016 ASH Annual Meeting, abstract 3026

Gilles Salles, MD, PhD

The chimeric antigen receptor (CAR) T-cell therapy CTL019 produced a high response rate in a phase 2 trial of adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to researchers.

An interim analysis of the JULIET trial revealed a 3-month overall response rate (ORR) of 45%.

Thirty-seven percent of patients had a complete response (CR), and all of the patients who were in CR at 3 months were still in CR at the data cutoff point.

This confirms the high response rates and durable responses observed in a previous single-center trial*, said JULIET investigator Gilles Salles, MD, PhD, of Hospices Civils de Lyon in Lyon, France.

Dr Salles presented results from JULIET at the 22nd Congress of the European Hematology Association (EHA) in Madrid, Spain (abstract LB2604).

The results were also presented at the 14th International Conference on Malignant Lymphoma (ICML) in Lugano, Switzerland (abstract 007).

The study was sponsored by Novartis.

Patients

JULIET enrolled 141 patients age 18 and older with relapsed/refractory DLBCL.

Forty-three patients discontinued the study before receiving CTL019—28 due to progressive disease (including 16 deaths), 9 due to an inability to manufacture CTL019, 2 due to adverse events, 1 due to investigator decision, 1 due to study withdrawal, and 1 due to protocol deviation.

Eighty-five patients were infused. The remaining 13 patients were pending infusion at the data cutoff—December 20, 2016.

The median age of the 85 infused patients was 56 (range, 24-75). Ninety-six percent of patients had DLBCL not otherwise specified. Fifty-one percent had germinal center B-cell type DLBCL.

Fifty-four percent of patients had an ECOG performance status of 0, and 46% had a status of 1. Fifty-three percent of patients had stage IV disease, and 8% had bone marrow involvement.

Forty percent of patients had 2 prior lines of antineoplastic therapy, 29% had 3, and 31% had 4 to 7 prior lines.

Forty-one percent of patients were refractory to their last therapy, and 59% had relapsed after their last therapy. Fifty-one percent of patients had prior autologous stem cell transplant.

Treatment

Seventy-six patients (89%) received bridging chemotherapy to prevent disease progression during CTL019 manufacturing. This treatment was completed 2 to 14 days prior to CTL019 infusion.

The median CTL019 cell dose was 3.1 x 10⁸ (range, 0.1-6.0 x 10⁸).

Response

Fifty-one patients were evaluated for response. The median time from infusion to data cutoff was 3.7 months.

The best ORR was 59%, with a CR rate of 43% and a partial response rate of 16%. Twelve percent of patients had stable disease, and 24% progressed.

At 3 months, the ORR was 45%. The CR rate was 37%, and the partial response rate was 8%.

“All patients in CR at 3 months remained in CR at follow-up, and the median duration of response was not reached,” Dr Salles noted.

None of the responders went on to receive a transplant.

Safety

All 85 patients were evaluated for safety. Adverse events of special interest, occurring within 8 weeks of CTL019 infusion, were:

• Cytokine release syndrome—57% all grades, 17% grade 3, 9% grade 4
• Infections—27% all grades, 12% grade 3, 1% grade 4
• Cytopenias not resolved by day 28—26% all grades, 13% grade 3, 8% grade 4
• Neurologic events—21% all grades, 9% grade 3, 4% grade 4
• Febrile neutropenia—14% all grades, 13% grade 3, 1% grade 4
• Tumor lysis syndrome—1% grade 3.

“Adverse events were reversible and effectively managed at the different centers by appropriately trained study personnel,” Dr Salles noted. “There were no CTL019-related deaths and no cerebral edema.”

*SJ Schuster et al, 2016 ASH Annual Meeting, abstract 3026

Photo by Patrick Pelletier

MADRID—Results of the DESTINY trial suggest that chronic myeloid leukemia (CML) patients may improve their chances of successfully stopping treatment with tyrosine kinase inhibitors (TKIs) by first reducing the dose they receive.

CML patients in deep molecular response (MR4) at study entry had a low rate of recurrence when they first de-escalated their TKI dose—receiving half the standard dose—for a year and then completely stopped receiving TKI treatment for a year.

The 2-year recurrence-free survival (RFS) rate was 77%, which is better than the RFS in any comparable study to date, according to Richard Clark, MD, of the University of Liverpool in Liverpool, UK, and his colleagues.

Dr Clark presented results from DESTINY at the 22nd Congress of the European Hematology Association (EHA) as abstract S423.

DESTINY included 174 CML patients (98 male, 76 female) in stable major molecular response (MMR).

At study entry, patients had received imatinib (n=148), nilotinib (n=16), or dasatinib (n=10) for a median duration of 6.8 years.

For the first 12 months of the study, patients had their TKI dose reduced to half the standard dose. So they received imatinib at 200 mg daily, dasatinib at 50 mg daily, or nilotinib at 200 mg twice daily. After that, patients stopped treatment completely.

After the first 12 months, molecular recurrence was lower in patients with stable MR4 at study entry than in patients who were not in MR4 (but still in MMR)—2.4% (3/125) and 18.4% (9/49), respectively (P<0.001).

During the following 12 months, in which patients had completely stopped TKI treatment, there were 26 recurrences and 4 withdrawals among the remaining 117 patients who were in MR4 at baseline, as well as 20 recurrences and 4 withdrawals among the 36 patients not in MR4.

So the RFS was 77% among patients in MR4 at baseline and 39% among the patients not in MR4 (P<0.001).

The researchers said the probability of RFS was unrelated to patients’ age, gender, performance status, or the prior TKI they received (imatinib vs second-generation TKI).

All patients with recurrence ultimately returned to deep remissions when they resumed their TKI treatment.

“TKI de-escalation is safe for most CML patients with stable and excellent responses to TKI therapy after some years of treatment and is associated with improvement in symptoms,” Dr Clark said.

“Overall, our findings are better than any other studies worldwide and imply that our unique, gradual withdrawal of treatment might be important. We don’t yet understand why our results are so good, but this is a happy problem to have.”

Photo by Patrick Pelletier

MADRID—Results of the DESTINY trial suggest that chronic myeloid leukemia (CML) patients may improve their chances of successfully stopping treatment with tyrosine kinase inhibitors (TKIs) by first reducing the dose they receive.

CML patients in deep molecular response (MR4) at study entry had a low rate of recurrence when they first de-escalated their TKI dose—receiving half the standard dose—for a year and then completely stopped receiving TKI treatment for a year.

The 2-year recurrence-free survival (RFS) rate was 77%, which is better than the RFS in any comparable study to date, according to Richard Clark, MD, of the University of Liverpool in Liverpool, UK, and his colleagues.

Dr Clark presented results from DESTINY at the 22nd Congress of the European Hematology Association (EHA) as abstract S423.

DESTINY included 174 CML patients (98 male, 76 female) in stable major molecular response (MMR).

At study entry, patients had received imatinib (n=148), nilotinib (n=16), or dasatinib (n=10) for a median duration of 6.8 years.

For the first 12 months of the study, patients had their TKI dose reduced to half the standard dose. So they received imatinib at 200 mg daily, dasatinib at 50 mg daily, or nilotinib at 200 mg twice daily. After that, patients stopped treatment completely.

After the first 12 months, molecular recurrence was lower in patients with stable MR4 at study entry than in patients who were not in MR4 (but still in MMR)—2.4% (3/125) and 18.4% (9/49), respectively (P<0.001).

During the following 12 months, in which patients had completely stopped TKI treatment, there were 26 recurrences and 4 withdrawals among the remaining 117 patients who were in MR4 at baseline, as well as 20 recurrences and 4 withdrawals among the 36 patients not in MR4.

So the RFS was 77% among patients in MR4 at baseline and 39% among the patients not in MR4 (P<0.001).

The researchers said the probability of RFS was unrelated to patients’ age, gender, performance status, or the prior TKI they received (imatinib vs second-generation TKI).

All patients with recurrence ultimately returned to deep remissions when they resumed their TKI treatment.

“TKI de-escalation is safe for most CML patients with stable and excellent responses to TKI therapy after some years of treatment and is associated with improvement in symptoms,” Dr Clark said.

“Overall, our findings are better than any other studies worldwide and imply that our unique, gradual withdrawal of treatment might be important. We don’t yet understand why our results are so good, but this is a happy problem to have.”

Photo by Patrick Pelletier

MADRID—Results of the DESTINY trial suggest that chronic myeloid leukemia (CML) patients may improve their chances of successfully stopping treatment with tyrosine kinase inhibitors (TKIs) by first reducing the dose they receive.

CML patients in deep molecular response (MR4) at study entry had a low rate of recurrence when they first de-escalated their TKI dose—receiving half the standard dose—for a year and then completely stopped receiving TKI treatment for a year.

The 2-year recurrence-free survival (RFS) rate was 77%, which is better than the RFS in any comparable study to date, according to Richard Clark, MD, of the University of Liverpool in Liverpool, UK, and his colleagues.

Dr Clark presented results from DESTINY at the 22nd Congress of the European Hematology Association (EHA) as abstract S423.

DESTINY included 174 CML patients (98 male, 76 female) in stable major molecular response (MMR).

At study entry, patients had received imatinib (n=148), nilotinib (n=16), or dasatinib (n=10) for a median duration of 6.8 years.

For the first 12 months of the study, patients had their TKI dose reduced to half the standard dose. So they received imatinib at 200 mg daily, dasatinib at 50 mg daily, or nilotinib at 200 mg twice daily. After that, patients stopped treatment completely.

After the first 12 months, molecular recurrence was lower in patients with stable MR4 at study entry than in patients who were not in MR4 (but still in MMR)—2.4% (3/125) and 18.4% (9/49), respectively (P<0.001).

During the following 12 months, in which patients had completely stopped TKI treatment, there were 26 recurrences and 4 withdrawals among the remaining 117 patients who were in MR4 at baseline, as well as 20 recurrences and 4 withdrawals among the 36 patients not in MR4.

So the RFS was 77% among patients in MR4 at baseline and 39% among the patients not in MR4 (P<0.001).

The researchers said the probability of RFS was unrelated to patients’ age, gender, performance status, or the prior TKI they received (imatinib vs second-generation TKI).

All patients with recurrence ultimately returned to deep remissions when they resumed their TKI treatment.

“TKI de-escalation is safe for most CML patients with stable and excellent responses to TKI therapy after some years of treatment and is associated with improvement in symptoms,” Dr Clark said.

“Overall, our findings are better than any other studies worldwide and imply that our unique, gradual withdrawal of treatment might be important. We don’t yet understand why our results are so good, but this is a happy problem to have.”

MADRID – Monotherapy with the investigational oral agent enasidenib was associated with comparatively high response rates among patients with heavily pretreated relapsed or refractory acute myeloid leukemia (AML) and IDH2 mutations in a phase 1/2 study.

Among 214 patients treated at a dose level of 100 mg daily, the overall response rate was 37%, including 20.1% complete responses (CRs) and 7.9% complete responses with incomplete recovery of platelets (CRp) or incomplete hematologic recovery (CRi), reported Eytan M. Stein, MD, an internist and hematologic oncologist at the Memorial Sloan Kettering Cancer Center in New York.

“In patients with relapsed/refractory AML (with IDH2 mutations), most of whom had received multiple prior AML treatments, enasidenib induced durable CRs that were associated with overall survival of greater than 8 months,” he said at the annual congress of the European Hematology Association.

The IDH2 gene encodes for isocitrate dehydrogenase 2, which is an enzyme of the citric acid cycle. An estimated 8%-15% of patients with AML have mutations in IDH2 that cause intracellular accumulation of beta-hydroxyglutarate, which leads to blockage of myeloblast differentiation through a variety of mechanisms. The primary mechanism of action of enasidenib appears to be through its action on differentiation, rather than through cytotoxicity, Dr. Stein said.

He reported updated results from the fully enrolled cohorts of the phase 1/2 study. Earlier data from the study were reported at the 2017 annual meeting of the American Society of Clinical Oncology and in a paper published concurrently in Blood.

In the study, the investigators first enrolled 113 patients with advanced hematologic malignancies with IDH2 mutations and treated them with cumulative daily doses of enasidenib ranging from 50 to 650 mg.

In a phase 1 expansion study at the established dose of 100 mg daily, 126 patients with IDH2 mutations were enrolled in one of four cohorts: patients aged 60 or older with relapsed or refractory AML or AML patients of any age who experienced a relapse after undergoing a bone marrow transplant (BMT); patients under age 60 except those with post-BMT relapses; patients with previously untreated AML who were 60 years or older who declined the standard of care; and patients with other hematologic malignancies who were ineligible for other study arms.

The study also included a phase 2 expansion cohort of 106 patients with relapsed/refractory AML with IDH2 mutations treated with enasidenib 100 mg daily. The data cutoff was Oct. 14, 2016.

Among 214 patients treated at the 100-mg/day dose, the ORR was 37%, including 20.1% with a CR, 7.9% with a CRp or CRi, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state.

The median time to first response was 1.9 months, and the median time to CR was 3.7 months.

Clinicians should wait until patients have received at least four cycles of the drug before determining whether they should be continued on the drug or switched to another therapy, Dr. Stein said.

After 30 months of follow-up, overall survival (OS) among the 281 patients with relapsed/refractory AML with IDH2 mutations who were treated with enasidenib at any dose level was 8.4 months. Among the 214 treated at the 100-mg daily dose level, the median OS was 8.3 months.

When the investigators looked at OS by best response, they saw that patients who had a CR had a median OS of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months.

Patients generally tolerated the drug well. Most adverse events were grade 1 or 2 in severity.

An increase in blood bilirubin was the most frequent grade 3 or 4 adverse event, occurring in 8% of all patients. The effect was caused by an off-target reaction and was not associated with elevations in liver enzymes or evidence of liver damage, Dr. Stein said.

Grade 3 or 4 dyspnea occurred in 6% of patients, and 7% of all patients had serious treatment-related IDH-inhibitor–associated differentiation syndrome (IDH-DS). This syndrome presents with symptoms similar to those of retinoic acid syndrome, which occurs during treatment for acute promyelocytic leukemia.

Enasidenib is being explored in a phase 3 study comparing enasidenib monotherapy with conventional care in patients with late-stage AML and in combination with other agents and regimens in phase 1/2 studies in patients with newly diagnosed AML with IDH2 mutations.

Enasidenib has been granted priority review by the U.S. Food and Drug Administration for relapsed/refractory AML with an IDH2 mutation and has been given a Prescription Drug User Fee Act action date of Aug. 30, 2017, according to Celgene.

The study was funded by Celgene. Dr. Stein disclosed a consulting/advisory role with the company, research funding, and travel expenses.

MADRID – Monotherapy with the investigational oral agent enasidenib was associated with comparatively high response rates among patients with heavily pretreated relapsed or refractory acute myeloid leukemia (AML) and IDH2 mutations in a phase 1/2 study.

Among 214 patients treated at a dose level of 100 mg daily, the overall response rate was 37%, including 20.1% complete responses (CRs) and 7.9% complete responses with incomplete recovery of platelets (CRp) or incomplete hematologic recovery (CRi), reported Eytan M. Stein, MD, an internist and hematologic oncologist at the Memorial Sloan Kettering Cancer Center in New York.

“In patients with relapsed/refractory AML (with IDH2 mutations), most of whom had received multiple prior AML treatments, enasidenib induced durable CRs that were associated with overall survival of greater than 8 months,” he said at the annual congress of the European Hematology Association.

The IDH2 gene encodes for isocitrate dehydrogenase 2, which is an enzyme of the citric acid cycle. An estimated 8%-15% of patients with AML have mutations in IDH2 that cause intracellular accumulation of beta-hydroxyglutarate, which leads to blockage of myeloblast differentiation through a variety of mechanisms. The primary mechanism of action of enasidenib appears to be through its action on differentiation, rather than through cytotoxicity, Dr. Stein said.

He reported updated results from the fully enrolled cohorts of the phase 1/2 study. Earlier data from the study were reported at the 2017 annual meeting of the American Society of Clinical Oncology and in a paper published concurrently in Blood.

In the study, the investigators first enrolled 113 patients with advanced hematologic malignancies with IDH2 mutations and treated them with cumulative daily doses of enasidenib ranging from 50 to 650 mg.

In a phase 1 expansion study at the established dose of 100 mg daily, 126 patients with IDH2 mutations were enrolled in one of four cohorts: patients aged 60 or older with relapsed or refractory AML or AML patients of any age who experienced a relapse after undergoing a bone marrow transplant (BMT); patients under age 60 except those with post-BMT relapses; patients with previously untreated AML who were 60 years or older who declined the standard of care; and patients with other hematologic malignancies who were ineligible for other study arms.

The study also included a phase 2 expansion cohort of 106 patients with relapsed/refractory AML with IDH2 mutations treated with enasidenib 100 mg daily. The data cutoff was Oct. 14, 2016.

Among 214 patients treated at the 100-mg/day dose, the ORR was 37%, including 20.1% with a CR, 7.9% with a CRp or CRi, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state.

The median time to first response was 1.9 months, and the median time to CR was 3.7 months.

Clinicians should wait until patients have received at least four cycles of the drug before determining whether they should be continued on the drug or switched to another therapy, Dr. Stein said.

After 30 months of follow-up, overall survival (OS) among the 281 patients with relapsed/refractory AML with IDH2 mutations who were treated with enasidenib at any dose level was 8.4 months. Among the 214 treated at the 100-mg daily dose level, the median OS was 8.3 months.

When the investigators looked at OS by best response, they saw that patients who had a CR had a median OS of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months.

Patients generally tolerated the drug well. Most adverse events were grade 1 or 2 in severity.

An increase in blood bilirubin was the most frequent grade 3 or 4 adverse event, occurring in 8% of all patients. The effect was caused by an off-target reaction and was not associated with elevations in liver enzymes or evidence of liver damage, Dr. Stein said.

Grade 3 or 4 dyspnea occurred in 6% of patients, and 7% of all patients had serious treatment-related IDH-inhibitor–associated differentiation syndrome (IDH-DS). This syndrome presents with symptoms similar to those of retinoic acid syndrome, which occurs during treatment for acute promyelocytic leukemia.

Enasidenib is being explored in a phase 3 study comparing enasidenib monotherapy with conventional care in patients with late-stage AML and in combination with other agents and regimens in phase 1/2 studies in patients with newly diagnosed AML with IDH2 mutations.

Enasidenib has been granted priority review by the U.S. Food and Drug Administration for relapsed/refractory AML with an IDH2 mutation and has been given a Prescription Drug User Fee Act action date of Aug. 30, 2017, according to Celgene.

The study was funded by Celgene. Dr. Stein disclosed a consulting/advisory role with the company, research funding, and travel expenses.

MADRID – Monotherapy with the investigational oral agent enasidenib was associated with comparatively high response rates among patients with heavily pretreated relapsed or refractory acute myeloid leukemia (AML) and IDH2 mutations in a phase 1/2 study.

Among 214 patients treated at a dose level of 100 mg daily, the overall response rate was 37%, including 20.1% complete responses (CRs) and 7.9% complete responses with incomplete recovery of platelets (CRp) or incomplete hematologic recovery (CRi), reported Eytan M. Stein, MD, an internist and hematologic oncologist at the Memorial Sloan Kettering Cancer Center in New York.

“In patients with relapsed/refractory AML (with IDH2 mutations), most of whom had received multiple prior AML treatments, enasidenib induced durable CRs that were associated with overall survival of greater than 8 months,” he said at the annual congress of the European Hematology Association.

The IDH2 gene encodes for isocitrate dehydrogenase 2, which is an enzyme of the citric acid cycle. An estimated 8%-15% of patients with AML have mutations in IDH2 that cause intracellular accumulation of beta-hydroxyglutarate, which leads to blockage of myeloblast differentiation through a variety of mechanisms. The primary mechanism of action of enasidenib appears to be through its action on differentiation, rather than through cytotoxicity, Dr. Stein said.

He reported updated results from the fully enrolled cohorts of the phase 1/2 study. Earlier data from the study were reported at the 2017 annual meeting of the American Society of Clinical Oncology and in a paper published concurrently in Blood.

In the study, the investigators first enrolled 113 patients with advanced hematologic malignancies with IDH2 mutations and treated them with cumulative daily doses of enasidenib ranging from 50 to 650 mg.

In a phase 1 expansion study at the established dose of 100 mg daily, 126 patients with IDH2 mutations were enrolled in one of four cohorts: patients aged 60 or older with relapsed or refractory AML or AML patients of any age who experienced a relapse after undergoing a bone marrow transplant (BMT); patients under age 60 except those with post-BMT relapses; patients with previously untreated AML who were 60 years or older who declined the standard of care; and patients with other hematologic malignancies who were ineligible for other study arms.

The study also included a phase 2 expansion cohort of 106 patients with relapsed/refractory AML with IDH2 mutations treated with enasidenib 100 mg daily. The data cutoff was Oct. 14, 2016.

Among 214 patients treated at the 100-mg/day dose, the ORR was 37%, including 20.1% with a CR, 7.9% with a CRp or CRi, 3.7% with partial responses, and 5.1% with a morphologic leukemia-free state.

The median time to first response was 1.9 months, and the median time to CR was 3.7 months.

Clinicians should wait until patients have received at least four cycles of the drug before determining whether they should be continued on the drug or switched to another therapy, Dr. Stein said.

After 30 months of follow-up, overall survival (OS) among the 281 patients with relapsed/refractory AML with IDH2 mutations who were treated with enasidenib at any dose level was 8.4 months. Among the 214 treated at the 100-mg daily dose level, the median OS was 8.3 months.

When the investigators looked at OS by best response, they saw that patients who had a CR had a median OS of 22.9 months. For patients with responses other than CR, the median OS was 15.1 months. For patients with no response to the drug, the median OS was 5.6 months.

Patients generally tolerated the drug well. Most adverse events were grade 1 or 2 in severity.

An increase in blood bilirubin was the most frequent grade 3 or 4 adverse event, occurring in 8% of all patients. The effect was caused by an off-target reaction and was not associated with elevations in liver enzymes or evidence of liver damage, Dr. Stein said.

Grade 3 or 4 dyspnea occurred in 6% of patients, and 7% of all patients had serious treatment-related IDH-inhibitor–associated differentiation syndrome (IDH-DS). This syndrome presents with symptoms similar to those of retinoic acid syndrome, which occurs during treatment for acute promyelocytic leukemia.

Enasidenib is being explored in a phase 3 study comparing enasidenib monotherapy with conventional care in patients with late-stage AML and in combination with other agents and regimens in phase 1/2 studies in patients with newly diagnosed AML with IDH2 mutations.

Enasidenib has been granted priority review by the U.S. Food and Drug Administration for relapsed/refractory AML with an IDH2 mutation and has been given a Prescription Drug User Fee Act action date of Aug. 30, 2017, according to Celgene.

The study was funded by Celgene. Dr. Stein disclosed a consulting/advisory role with the company, research funding, and travel expenses.

Photo from UAB Hospital

MADRID—Results of a phase 2 study have shown that luspatercept can produce sustained increases in hemoglobin and reductions in transfusion burden in adults with β-thalassemia.

Some patients are still receiving the drug and experiencing clinical benefits beyond 24 months.

Luspatercept has been well-tolerated in these patients, producing no serious adverse events (AEs).

“Luspatercept has many characteristics that are promising . . .,” said Antonio G. Piga, MD, of Turin University in Turin, Italy.

He presented results of the phase 2 study at the 22nd Congress of the European Hematology Association (EHA) as abstract S129.

The study was sponsored by Celgene in collaboration with Acceleron Pharma.

Dr Piga presented data on 63 patients—32 of whom were transfusion-dependent (TD) and 31 of whom were non-transfusion-dependent (NTD).

For the entire study cohort, the median age was 38 (range, 20-62), 52% of patients were male, and 67% had undergone a splenectomy.

In the NTD patients, the median hemoglobin at baseline was 8.5 g/dL (range, 6.5-9.8).

The TD patients received a median of 8 (range, 4-18) red blood cell (RBC) units every 12 weeks.

For the 3-month base study, patients received luspatercept at 0.2 mg/kg to 1.25 mg/kg every 3 weeks.

In the ongoing extension study, patients can receive luspatercept at 0.8 mg/kg to 1.25 mg/kg every 3 weeks for up to 5 years.

Efficacy in NTD patients

The median duration of treatment for NTD patients (n=31) was 18.6 months (range, 1.3-29.4 months; ongoing).

Over a 12-week period, 71% (22/31) of NTD patients saw at least a 1.0 g/dL increase in mean hemoglobin from baseline. Fifty-two percent (16/31) saw an increase of 1.5 g/dL or greater.

To assess quality of life in NTD patients, the researchers used FACIT-F, a 13-item questionnaire used to assess anemia-related symptoms such as fatigue and weakness.

Fifty-eight percent (7/12) of patients with a baseline FACIT-F deficit (<44 points) had improved by at least 3 points at 48 weeks.

And 86% (6/7) of patients with at least a 3-point increase in FACIT-F score had at least a 1.0 g/dL improvement in mean hemoglobin over a 12-week period.

Efficacy in TD patients

The median duration of treatment for TD patients was 14.2 months (range, 0.7-27.2 months, ongoing).

Seventy-eight percent (25/32) of these patients had at least a 20% reduction in RBC units transfused from 12 weeks pre-treatment to any 12-week interval on treatment. Sixty-nine percent (22/32) had at least a 33% reduction at any 12-week interval.

Fifty percent of patients (12/24) who received an estimated 6 to 20 RBC units every 24 weeks achieved a reduction in transfusion burden from baseline of at least 33% in the fixed 12-week interval from weeks 13 to 24.

Forty-six percent (11/24) achieved a reduction in transfusion burden from baseline of at least 33% in the interval from weeks 37 to 48.

Safety

The most common AEs possibly or probably related to luspatercept were bone pain (38%), headache (28%), myalgia (22%), arthralgia (19%), musculoskeletal pain (17%), asthenia (14%), injection site pain (13%), and back pain (11%).

Most AEs were grade 1 or 2 in severity. Treatment-related grade 3 AEs included bone pain (n=3), asthenia (n=2), and headache (n=1).

Dr Piga said these results support an ongoing phase 3 study of luspatercept in regularly transfused patients with β-thalassemia (BELIEVE, NCT02604433), which recently completed enrollment.

Photo from UAB Hospital

MADRID—Results of a phase 2 study have shown that luspatercept can produce sustained increases in hemoglobin and reductions in transfusion burden in adults with β-thalassemia.

Some patients are still receiving the drug and experiencing clinical benefits beyond 24 months.

Luspatercept has been well-tolerated in these patients, producing no serious adverse events (AEs).

“Luspatercept has many characteristics that are promising . . .,” said Antonio G. Piga, MD, of Turin University in Turin, Italy.

He presented results of the phase 2 study at the 22nd Congress of the European Hematology Association (EHA) as abstract S129.

The study was sponsored by Celgene in collaboration with Acceleron Pharma.

Dr Piga presented data on 63 patients—32 of whom were transfusion-dependent (TD) and 31 of whom were non-transfusion-dependent (NTD).

For the entire study cohort, the median age was 38 (range, 20-62), 52% of patients were male, and 67% had undergone a splenectomy.

In the NTD patients, the median hemoglobin at baseline was 8.5 g/dL (range, 6.5-9.8).

The TD patients received a median of 8 (range, 4-18) red blood cell (RBC) units every 12 weeks.

For the 3-month base study, patients received luspatercept at 0.2 mg/kg to 1.25 mg/kg every 3 weeks.

In the ongoing extension study, patients can receive luspatercept at 0.8 mg/kg to 1.25 mg/kg every 3 weeks for up to 5 years.

Efficacy in NTD patients

The median duration of treatment for NTD patients (n=31) was 18.6 months (range, 1.3-29.4 months; ongoing).

Over a 12-week period, 71% (22/31) of NTD patients saw at least a 1.0 g/dL increase in mean hemoglobin from baseline. Fifty-two percent (16/31) saw an increase of 1.5 g/dL or greater.

To assess quality of life in NTD patients, the researchers used FACIT-F, a 13-item questionnaire used to assess anemia-related symptoms such as fatigue and weakness.

Fifty-eight percent (7/12) of patients with a baseline FACIT-F deficit (<44 points) had improved by at least 3 points at 48 weeks.

And 86% (6/7) of patients with at least a 3-point increase in FACIT-F score had at least a 1.0 g/dL improvement in mean hemoglobin over a 12-week period.

Efficacy in TD patients

The median duration of treatment for TD patients was 14.2 months (range, 0.7-27.2 months, ongoing).

Seventy-eight percent (25/32) of these patients had at least a 20% reduction in RBC units transfused from 12 weeks pre-treatment to any 12-week interval on treatment. Sixty-nine percent (22/32) had at least a 33% reduction at any 12-week interval.

Fifty percent of patients (12/24) who received an estimated 6 to 20 RBC units every 24 weeks achieved a reduction in transfusion burden from baseline of at least 33% in the fixed 12-week interval from weeks 13 to 24.

Forty-six percent (11/24) achieved a reduction in transfusion burden from baseline of at least 33% in the interval from weeks 37 to 48.

Safety

The most common AEs possibly or probably related to luspatercept were bone pain (38%), headache (28%), myalgia (22%), arthralgia (19%), musculoskeletal pain (17%), asthenia (14%), injection site pain (13%), and back pain (11%).

Most AEs were grade 1 or 2 in severity. Treatment-related grade 3 AEs included bone pain (n=3), asthenia (n=2), and headache (n=1).

Dr Piga said these results support an ongoing phase 3 study of luspatercept in regularly transfused patients with β-thalassemia (BELIEVE, NCT02604433), which recently completed enrollment.

Photo from UAB Hospital

MADRID—Results of a phase 2 study have shown that luspatercept can produce sustained increases in hemoglobin and reductions in transfusion burden in adults with β-thalassemia.

Some patients are still receiving the drug and experiencing clinical benefits beyond 24 months.

Luspatercept has been well-tolerated in these patients, producing no serious adverse events (AEs).

“Luspatercept has many characteristics that are promising . . .,” said Antonio G. Piga, MD, of Turin University in Turin, Italy.

He presented results of the phase 2 study at the 22nd Congress of the European Hematology Association (EHA) as abstract S129.

The study was sponsored by Celgene in collaboration with Acceleron Pharma.

Dr Piga presented data on 63 patients—32 of whom were transfusion-dependent (TD) and 31 of whom were non-transfusion-dependent (NTD).

For the entire study cohort, the median age was 38 (range, 20-62), 52% of patients were male, and 67% had undergone a splenectomy.

In the NTD patients, the median hemoglobin at baseline was 8.5 g/dL (range, 6.5-9.8).

The TD patients received a median of 8 (range, 4-18) red blood cell (RBC) units every 12 weeks.

For the 3-month base study, patients received luspatercept at 0.2 mg/kg to 1.25 mg/kg every 3 weeks.

In the ongoing extension study, patients can receive luspatercept at 0.8 mg/kg to 1.25 mg/kg every 3 weeks for up to 5 years.

Efficacy in NTD patients

The median duration of treatment for NTD patients (n=31) was 18.6 months (range, 1.3-29.4 months; ongoing).

Over a 12-week period, 71% (22/31) of NTD patients saw at least a 1.0 g/dL increase in mean hemoglobin from baseline. Fifty-two percent (16/31) saw an increase of 1.5 g/dL or greater.

To assess quality of life in NTD patients, the researchers used FACIT-F, a 13-item questionnaire used to assess anemia-related symptoms such as fatigue and weakness.

Fifty-eight percent (7/12) of patients with a baseline FACIT-F deficit (<44 points) had improved by at least 3 points at 48 weeks.

And 86% (6/7) of patients with at least a 3-point increase in FACIT-F score had at least a 1.0 g/dL improvement in mean hemoglobin over a 12-week period.

Efficacy in TD patients

The median duration of treatment for TD patients was 14.2 months (range, 0.7-27.2 months, ongoing).

Seventy-eight percent (25/32) of these patients had at least a 20% reduction in RBC units transfused from 12 weeks pre-treatment to any 12-week interval on treatment. Sixty-nine percent (22/32) had at least a 33% reduction at any 12-week interval.

Fifty percent of patients (12/24) who received an estimated 6 to 20 RBC units every 24 weeks achieved a reduction in transfusion burden from baseline of at least 33% in the fixed 12-week interval from weeks 13 to 24.

Forty-six percent (11/24) achieved a reduction in transfusion burden from baseline of at least 33% in the interval from weeks 37 to 48.

Safety

The most common AEs possibly or probably related to luspatercept were bone pain (38%), headache (28%), myalgia (22%), arthralgia (19%), musculoskeletal pain (17%), asthenia (14%), injection site pain (13%), and back pain (11%).

Most AEs were grade 1 or 2 in severity. Treatment-related grade 3 AEs included bone pain (n=3), asthenia (n=2), and headache (n=1).

Dr Piga said these results support an ongoing phase 3 study of luspatercept in regularly transfused patients with β-thalassemia (BELIEVE, NCT02604433), which recently completed enrollment.

Congress of EHA

An all-oral treatment regimen can produce deep and durable responses in patients with newly diagnosed multiple myeloma (MM), according to a speaker at the 22nd Congress of the European Hematology Association (EHA).

In a phase 1/2 study, patients with newly diagnosed MM received treatment with ixazomib, lenalidomide, and dexamethasone for up to 12 cycles, followed by maintenance with ixazomib alone.

The overall response rate was 88% for the entire cohort and 80% among patients who did not proceed to transplant.

The median progression-free survival was 35.4 months in the entire cohort and 29.4 months in patients who did not proceed to transplant.

Most patients did not complete all 12 cycles of induction, but 38% proceeded to maintenance, and 12% remain on study treatment at a median follow-up of 56 months.

Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, presented these results at the EHA Congress as abstract S408. The research was sponsored by Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Limited.

Patients

The trial included 65 patients. Their median age was 66 (range, 34-86), and 55% were male. Eight percent of patients had high-risk cytogenetics.

ECOG performance status was 0 for 43% of patients, 1 for 52%, and 2 for 5%. ISS stage was 1 for 43% of patients, 2 for 43%, and 3 for 14%.

Treatment

Patients received ixazomib (1.68 - 3.95 mg/m² in phase 1 and 4.0 mg in phase 2 on days 1, 8, and 15) plus lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, 15, and 22) for up to twelve, 28-day cycles. Patients could then receive ixazomib maintenance until disease progression or unacceptable toxicity.

Twenty-three patients (35%) discontinued induction to undergo hematopoietic stem cell transplant (HSCT).

Thirty-seven patients discontinued study treatment for other reasons—17 of them during induction. Twenty-one patients discontinued due to progressive disease, 9 due to adverse events (AEs), 5 due to patient withdrawal, 1 due to unsatisfactory response, and 1 due to other reasons.

Twenty-five patients completed induction and went on to receive ixazomib maintenance. Five patients remain on study treatment.

Safety

Seventy-eight percent of patients had a grade 3 or higher AE, 46% had a serious AE, 57% had an AE leading to dose reduction, and 15% had an AE leading to discontinuation of any of the study drugs. There were 2 on-study deaths.

The most common grade 3 or higher AEs were neutropenia, thrombocytopenia, diarrhea, back pain, vomiting, nausea, peripheral neuropathy, and rashes/eruptions/exanthems.

Efficacy

The overall response rate was 88% for the entire cohort and 80% among patients who did not go on to receive HSCT.

The complete response (CR) rates were 23% and 32%, respectively. Thirty four percent and 32%, respectively, had a very good partial response (VGPR). And 30% and 17%, respectively, had a partial response (PR).

Thirty-two percent of patients who received maintenance (n=8) had an improvement in their response during the maintenance phase.  Two patients went from a VGPR to a stringent CR, 3 went from a VGPR to a CR, 2 went from a VGPR to a near CR, and 1 went from a PR to a VGPR.

Sixteen patients were evaluated for minimal residual disease (MRD). Of the patients with a stringent CR/CR, 89% (8/9) were MRD-negative.

The median progression-free survival was 35.4 months in the entire cohort and 29.4 months in patients who did not proceed to HSCT. The 4-year overall survival rate was 84% and 82%, respectively.

“Long-term follow-up, a median follow-up of 56 months, with the combination of ixazomib, lenalidomide, and dexamethasone demonstrates that this is an efficacious regimen for newly diagnosed myeloma patients, with excellent tolerability, and something that can be maintained for a long period of time,” Dr Kumar said. “These results form the basis for an ongoing phase 3 program.”

Congress of EHA

An all-oral treatment regimen can produce deep and durable responses in patients with newly diagnosed multiple myeloma (MM), according to a speaker at the 22nd Congress of the European Hematology Association (EHA).

In a phase 1/2 study, patients with newly diagnosed MM received treatment with ixazomib, lenalidomide, and dexamethasone for up to 12 cycles, followed by maintenance with ixazomib alone.

The overall response rate was 88% for the entire cohort and 80% among patients who did not proceed to transplant.

The median progression-free survival was 35.4 months in the entire cohort and 29.4 months in patients who did not proceed to transplant.

Most patients did not complete all 12 cycles of induction, but 38% proceeded to maintenance, and 12% remain on study treatment at a median follow-up of 56 months.

Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, presented these results at the EHA Congress as abstract S408. The research was sponsored by Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Limited.

Patients

The trial included 65 patients. Their median age was 66 (range, 34-86), and 55% were male. Eight percent of patients had high-risk cytogenetics.

ECOG performance status was 0 for 43% of patients, 1 for 52%, and 2 for 5%. ISS stage was 1 for 43% of patients, 2 for 43%, and 3 for 14%.

Treatment

Patients received ixazomib (1.68 - 3.95 mg/m² in phase 1 and 4.0 mg in phase 2 on days 1, 8, and 15) plus lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, 15, and 22) for up to twelve, 28-day cycles. Patients could then receive ixazomib maintenance until disease progression or unacceptable toxicity.

Twenty-three patients (35%) discontinued induction to undergo hematopoietic stem cell transplant (HSCT).

Thirty-seven patients discontinued study treatment for other reasons—17 of them during induction. Twenty-one patients discontinued due to progressive disease, 9 due to adverse events (AEs), 5 due to patient withdrawal, 1 due to unsatisfactory response, and 1 due to other reasons.

Twenty-five patients completed induction and went on to receive ixazomib maintenance. Five patients remain on study treatment.

Safety

Seventy-eight percent of patients had a grade 3 or higher AE, 46% had a serious AE, 57% had an AE leading to dose reduction, and 15% had an AE leading to discontinuation of any of the study drugs. There were 2 on-study deaths.

The most common grade 3 or higher AEs were neutropenia, thrombocytopenia, diarrhea, back pain, vomiting, nausea, peripheral neuropathy, and rashes/eruptions/exanthems.

Efficacy

The overall response rate was 88% for the entire cohort and 80% among patients who did not go on to receive HSCT.

The complete response (CR) rates were 23% and 32%, respectively. Thirty four percent and 32%, respectively, had a very good partial response (VGPR). And 30% and 17%, respectively, had a partial response (PR).

Thirty-two percent of patients who received maintenance (n=8) had an improvement in their response during the maintenance phase.  Two patients went from a VGPR to a stringent CR, 3 went from a VGPR to a CR, 2 went from a VGPR to a near CR, and 1 went from a PR to a VGPR.

Sixteen patients were evaluated for minimal residual disease (MRD). Of the patients with a stringent CR/CR, 89% (8/9) were MRD-negative.

The median progression-free survival was 35.4 months in the entire cohort and 29.4 months in patients who did not proceed to HSCT. The 4-year overall survival rate was 84% and 82%, respectively.

“Long-term follow-up, a median follow-up of 56 months, with the combination of ixazomib, lenalidomide, and dexamethasone demonstrates that this is an efficacious regimen for newly diagnosed myeloma patients, with excellent tolerability, and something that can be maintained for a long period of time,” Dr Kumar said. “These results form the basis for an ongoing phase 3 program.”

Congress of EHA

An all-oral treatment regimen can produce deep and durable responses in patients with newly diagnosed multiple myeloma (MM), according to a speaker at the 22nd Congress of the European Hematology Association (EHA).

In a phase 1/2 study, patients with newly diagnosed MM received treatment with ixazomib, lenalidomide, and dexamethasone for up to 12 cycles, followed by maintenance with ixazomib alone.

The overall response rate was 88% for the entire cohort and 80% among patients who did not proceed to transplant.

The median progression-free survival was 35.4 months in the entire cohort and 29.4 months in patients who did not proceed to transplant.

Most patients did not complete all 12 cycles of induction, but 38% proceeded to maintenance, and 12% remain on study treatment at a median follow-up of 56 months.

Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota, presented these results at the EHA Congress as abstract S408. The research was sponsored by Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Limited.

Patients

The trial included 65 patients. Their median age was 66 (range, 34-86), and 55% were male. Eight percent of patients had high-risk cytogenetics.

ECOG performance status was 0 for 43% of patients, 1 for 52%, and 2 for 5%. ISS stage was 1 for 43% of patients, 2 for 43%, and 3 for 14%.

Treatment

Patients received ixazomib (1.68 - 3.95 mg/m² in phase 1 and 4.0 mg in phase 2 on days 1, 8, and 15) plus lenalidomide (25 mg on days 1-21), and dexamethasone (40 mg on days 1, 8, 15, and 22) for up to twelve, 28-day cycles. Patients could then receive ixazomib maintenance until disease progression or unacceptable toxicity.

Twenty-three patients (35%) discontinued induction to undergo hematopoietic stem cell transplant (HSCT).

Thirty-seven patients discontinued study treatment for other reasons—17 of them during induction. Twenty-one patients discontinued due to progressive disease, 9 due to adverse events (AEs), 5 due to patient withdrawal, 1 due to unsatisfactory response, and 1 due to other reasons.

Twenty-five patients completed induction and went on to receive ixazomib maintenance. Five patients remain on study treatment.

Safety

Seventy-eight percent of patients had a grade 3 or higher AE, 46% had a serious AE, 57% had an AE leading to dose reduction, and 15% had an AE leading to discontinuation of any of the study drugs. There were 2 on-study deaths.

The most common grade 3 or higher AEs were neutropenia, thrombocytopenia, diarrhea, back pain, vomiting, nausea, peripheral neuropathy, and rashes/eruptions/exanthems.

Efficacy

The overall response rate was 88% for the entire cohort and 80% among patients who did not go on to receive HSCT.

The complete response (CR) rates were 23% and 32%, respectively. Thirty four percent and 32%, respectively, had a very good partial response (VGPR). And 30% and 17%, respectively, had a partial response (PR).

Thirty-two percent of patients who received maintenance (n=8) had an improvement in their response during the maintenance phase.  Two patients went from a VGPR to a stringent CR, 3 went from a VGPR to a CR, 2 went from a VGPR to a near CR, and 1 went from a PR to a VGPR.

Sixteen patients were evaluated for minimal residual disease (MRD). Of the patients with a stringent CR/CR, 89% (8/9) were MRD-negative.

The median progression-free survival was 35.4 months in the entire cohort and 29.4 months in patients who did not proceed to HSCT. The 4-year overall survival rate was 84% and 82%, respectively.

“Long-term follow-up, a median follow-up of 56 months, with the combination of ixazomib, lenalidomide, and dexamethasone demonstrates that this is an efficacious regimen for newly diagnosed myeloma patients, with excellent tolerability, and something that can be maintained for a long period of time,” Dr Kumar said. “These results form the basis for an ongoing phase 3 program.”