Aggressive Lymphomas

Micrograph showing DLBCL

The European Medicines Agency (EMA) has granted polatuzumab vedotin access to the agency’s PRIority MEdicines (PRIME) program.

The access is for polatuzumab vedotin when used in combination with rituximab and bendamustine for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Polatuzumab vedotin is an anti-CD79b antibody drug conjugate consisting of an anti-CD79b monoclonal antibody that is linked to a microtubule-disrupting agent.

Polatuzumab vedotin is being developed by Roche utilizing Seattle Genetics’ technology.

The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.

Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

The acceptance of polatuzumab vedotin in the PRIME program was supported by results from the phase 2 component of the GO29365 study.

Results from this trial were recently presented at the 22nd Congress of the European Hematology Association (EHA) as abstract S468.

Micrograph showing DLBCL

The European Medicines Agency (EMA) has granted polatuzumab vedotin access to the agency’s PRIority MEdicines (PRIME) program.

The access is for polatuzumab vedotin when used in combination with rituximab and bendamustine for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Polatuzumab vedotin is an anti-CD79b antibody drug conjugate consisting of an anti-CD79b monoclonal antibody that is linked to a microtubule-disrupting agent.

Polatuzumab vedotin is being developed by Roche utilizing Seattle Genetics’ technology.

The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.

Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

The acceptance of polatuzumab vedotin in the PRIME program was supported by results from the phase 2 component of the GO29365 study.

Results from this trial were recently presented at the 22nd Congress of the European Hematology Association (EHA) as abstract S468.

Micrograph showing DLBCL

The European Medicines Agency (EMA) has granted polatuzumab vedotin access to the agency’s PRIority MEdicines (PRIME) program.

The access is for polatuzumab vedotin when used in combination with rituximab and bendamustine for the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Polatuzumab vedotin is an anti-CD79b antibody drug conjugate consisting of an anti-CD79b monoclonal antibody that is linked to a microtubule-disrupting agent.

Polatuzumab vedotin is being developed by Roche utilizing Seattle Genetics’ technology.

The goal of the EMA’s PRIME program is to accelerate the development of therapies that may offer a major advantage over existing treatments or benefit patients with no treatment options.

Through PRIME, the EMA offers early and enhanced support to developers in order to optimize development plans and speed regulatory evaluations to potentially bring therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

The acceptance of polatuzumab vedotin in the PRIME program was supported by results from the phase 2 component of the GO29365 study.

Results from this trial were recently presented at the 22nd Congress of the European Hematology Association (EHA) as abstract S468.

 

Diffuse large B-cell lymphoma

 

LUGANO, SWITZERLAND—The chimeric antigen receptor (CAR) T-cell therapy JCAR017 can produce “potent and durable” responses in patients with relapsed/refractory, aggressive diffuse large B-cell lymphoma (DLBCL), according to an investigator from the TRANSCEND NHL 001 trial.

 

In this phase 1 trial, JCAR017, given after lymphodepleting chemotherapy, produced an overall response rate (ORR) of 76% and a complete response (CR) rate of 52%.

 

At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.

 

Responses were seen even in poor-risk subgroups, noted study investigator Jeremy Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.

 

“TRANSCEND NHL 001 is the first multicenter study of a CD19-directed CAR T-cell product with a fixed CD4 and CD8 composition to deliver potent and durable responses in high-risk subsets in DLBCL,” Dr Abramson said.

 

He presented data from the trial at the 2017 International Conference on Malignant Lymphoma (ICML) as abstract 128. The research was sponsored by Juno Therapeutics, the company developing JCAR017.

 

Patients

 

Dr Abramson presented data on 55 patients with relapsed/refractory non-Hodgkin lymphoma. Forty patients had DLBCL not otherwise specified, 14 had transformed DLBCL, and 1 had grade 3B follicular lymphoma. Fifteen patients had double- or triple-hit lymphoma.

 

The patients’ median age was 61 (range, 29-82), and 69% were male. Eighty-seven percent of patients (n=48) had an ECOG status of 0 to 1. Two patients had central nervous system involvement.

 

The patients had received a median of 3 prior lines of therapy (range, 1-11). Seventy-six percent of patients (n=42) were chemo-refractory, 7% (n=4) had received an allogeneic transplant, and 44% (n=24) had received an autologous transplant.

 

Treatment

 

Patients received 1 of 2 doses of JCAR017 after fludarabine/cyclophosphamide lymphodepletion.

 

Thirty patients received a single dose of JCAR017 at 5 x 10⁷ CAR cells (dose-level 1, single [DL1S]).

 

Six patients received 2 doses of 5 x 10⁷ CAR cells (dose-level 1, double [DL1D]).

 

Nineteen patients received a single dose of 1 x 10⁸ CAR cells (dose-level 2, single [DL2S]).

 

Safety

 

More than 90% of patients experienced a treatment-emergent adverse event (AE), and 60% had a treatment-related AE.

 

Treatment-emergent AEs occurring in more than 20% of patients included cytokine release syndrome (CRS), fatigue, nausea, constipation, decreased appetite, diarrhea, hypotension, neutropenia, anemia, and thrombocytopenia.

 

One patient had a grade 5 AE of diffuse alveolar damage that was thought to be related to fludarabine, cyclophosphamide, and JCAR017.

 

Another patient had a grade 5 AE of multiorgan failure that was considered unrelated to study treatment and due to disease progression.

 

The rate of grade 1/2 CRS was 33% (n=18), and the rate of grade 3/4 CRS was 2% (n=1). The rate of grade 1/2 neurotoxicity was 6% (n=3), and the rate of grade 3/4 neurotoxicity was 16% (n=9).

 

There were no deaths from CRS or neurotoxicity. The median time to onset of CRS was 5 days (range, 1-23), and the median time to onset of neurotoxicity was 11 days (range, 5-23).

 

“JCAR017 toxicities have, thus far, been relatively low and highly manageable at all dose levels tested, with a favorable safety profile that may enable outpatient administration,” Dr Abramson said.

 

Response

 

Fifty-four patients were evaluable for response. The ORR was 76%, and the CR rate was 52%. At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.

 

Dr Abramson noted that there was a dose-response relationship.

 

Overall, in the DL1S cohort, the ORR was 80%, and the CR rate was 53%. In the DL2S cohort, the ORR was 72%, and the CR rate was 50%. In the DL1D cohort, the ORR was 67%, and the CR rate was 50%.

 

 

At 3 months, in the DL1S cohort, the ORR was 46%, and the CR rate was 33%. In the DL2S cohort, the ORR was 64%, and the CR rate was 46%. In the DL1D cohort, the ORR and CR rate were both 50%.

 

Dr Abramson also noted that JCAR017 could produce a high response rate in poor-risk subgroups.

 

At 3 months, the ORR was 91% in patients who relapsed less than 12 months after transplant, 82% in patients with double- or triple-hit lymphoma, 48% in patients who had never achieved a CR, 47% in chemo-refractory patients, 31% in patients with primary refractory lymphoma, and 24% in patients with stable disease or progression after last chemotherapy.

 

Diffuse large B-cell lymphoma

 

LUGANO, SWITZERLAND—The chimeric antigen receptor (CAR) T-cell therapy JCAR017 can produce “potent and durable” responses in patients with relapsed/refractory, aggressive diffuse large B-cell lymphoma (DLBCL), according to an investigator from the TRANSCEND NHL 001 trial.

 

In this phase 1 trial, JCAR017, given after lymphodepleting chemotherapy, produced an overall response rate (ORR) of 76% and a complete response (CR) rate of 52%.

 

At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.

 

Responses were seen even in poor-risk subgroups, noted study investigator Jeremy Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.

 

“TRANSCEND NHL 001 is the first multicenter study of a CD19-directed CAR T-cell product with a fixed CD4 and CD8 composition to deliver potent and durable responses in high-risk subsets in DLBCL,” Dr Abramson said.

 

He presented data from the trial at the 2017 International Conference on Malignant Lymphoma (ICML) as abstract 128. The research was sponsored by Juno Therapeutics, the company developing JCAR017.

 

Patients

 

Dr Abramson presented data on 55 patients with relapsed/refractory non-Hodgkin lymphoma. Forty patients had DLBCL not otherwise specified, 14 had transformed DLBCL, and 1 had grade 3B follicular lymphoma. Fifteen patients had double- or triple-hit lymphoma.

 

The patients’ median age was 61 (range, 29-82), and 69% were male. Eighty-seven percent of patients (n=48) had an ECOG status of 0 to 1. Two patients had central nervous system involvement.

 

The patients had received a median of 3 prior lines of therapy (range, 1-11). Seventy-six percent of patients (n=42) were chemo-refractory, 7% (n=4) had received an allogeneic transplant, and 44% (n=24) had received an autologous transplant.

 

Treatment

 

Patients received 1 of 2 doses of JCAR017 after fludarabine/cyclophosphamide lymphodepletion.

 

Thirty patients received a single dose of JCAR017 at 5 x 10⁷ CAR cells (dose-level 1, single [DL1S]).

 

Six patients received 2 doses of 5 x 10⁷ CAR cells (dose-level 1, double [DL1D]).

 

Nineteen patients received a single dose of 1 x 10⁸ CAR cells (dose-level 2, single [DL2S]).

 

Safety

 

More than 90% of patients experienced a treatment-emergent adverse event (AE), and 60% had a treatment-related AE.

 

Treatment-emergent AEs occurring in more than 20% of patients included cytokine release syndrome (CRS), fatigue, nausea, constipation, decreased appetite, diarrhea, hypotension, neutropenia, anemia, and thrombocytopenia.

 

One patient had a grade 5 AE of diffuse alveolar damage that was thought to be related to fludarabine, cyclophosphamide, and JCAR017.

 

Another patient had a grade 5 AE of multiorgan failure that was considered unrelated to study treatment and due to disease progression.

 

The rate of grade 1/2 CRS was 33% (n=18), and the rate of grade 3/4 CRS was 2% (n=1). The rate of grade 1/2 neurotoxicity was 6% (n=3), and the rate of grade 3/4 neurotoxicity was 16% (n=9).

 

There were no deaths from CRS or neurotoxicity. The median time to onset of CRS was 5 days (range, 1-23), and the median time to onset of neurotoxicity was 11 days (range, 5-23).

 

“JCAR017 toxicities have, thus far, been relatively low and highly manageable at all dose levels tested, with a favorable safety profile that may enable outpatient administration,” Dr Abramson said.

 

Response

 

Fifty-four patients were evaluable for response. The ORR was 76%, and the CR rate was 52%. At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.

 

Dr Abramson noted that there was a dose-response relationship.

 

Overall, in the DL1S cohort, the ORR was 80%, and the CR rate was 53%. In the DL2S cohort, the ORR was 72%, and the CR rate was 50%. In the DL1D cohort, the ORR was 67%, and the CR rate was 50%.

 

 

At 3 months, in the DL1S cohort, the ORR was 46%, and the CR rate was 33%. In the DL2S cohort, the ORR was 64%, and the CR rate was 46%. In the DL1D cohort, the ORR and CR rate were both 50%.

 

Dr Abramson also noted that JCAR017 could produce a high response rate in poor-risk subgroups.

 

At 3 months, the ORR was 91% in patients who relapsed less than 12 months after transplant, 82% in patients with double- or triple-hit lymphoma, 48% in patients who had never achieved a CR, 47% in chemo-refractory patients, 31% in patients with primary refractory lymphoma, and 24% in patients with stable disease or progression after last chemotherapy.

 

Diffuse large B-cell lymphoma

 

LUGANO, SWITZERLAND—The chimeric antigen receptor (CAR) T-cell therapy JCAR017 can produce “potent and durable” responses in patients with relapsed/refractory, aggressive diffuse large B-cell lymphoma (DLBCL), according to an investigator from the TRANSCEND NHL 001 trial.

 

In this phase 1 trial, JCAR017, given after lymphodepleting chemotherapy, produced an overall response rate (ORR) of 76% and a complete response (CR) rate of 52%.

 

At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.

 

Responses were seen even in poor-risk subgroups, noted study investigator Jeremy Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.

 

“TRANSCEND NHL 001 is the first multicenter study of a CD19-directed CAR T-cell product with a fixed CD4 and CD8 composition to deliver potent and durable responses in high-risk subsets in DLBCL,” Dr Abramson said.

 

He presented data from the trial at the 2017 International Conference on Malignant Lymphoma (ICML) as abstract 128. The research was sponsored by Juno Therapeutics, the company developing JCAR017.

 

Patients

 

Dr Abramson presented data on 55 patients with relapsed/refractory non-Hodgkin lymphoma. Forty patients had DLBCL not otherwise specified, 14 had transformed DLBCL, and 1 had grade 3B follicular lymphoma. Fifteen patients had double- or triple-hit lymphoma.

 

The patients’ median age was 61 (range, 29-82), and 69% were male. Eighty-seven percent of patients (n=48) had an ECOG status of 0 to 1. Two patients had central nervous system involvement.

 

The patients had received a median of 3 prior lines of therapy (range, 1-11). Seventy-six percent of patients (n=42) were chemo-refractory, 7% (n=4) had received an allogeneic transplant, and 44% (n=24) had received an autologous transplant.

 

Treatment

 

Patients received 1 of 2 doses of JCAR017 after fludarabine/cyclophosphamide lymphodepletion.

 

Thirty patients received a single dose of JCAR017 at 5 x 10⁷ CAR cells (dose-level 1, single [DL1S]).

 

Six patients received 2 doses of 5 x 10⁷ CAR cells (dose-level 1, double [DL1D]).

 

Nineteen patients received a single dose of 1 x 10⁸ CAR cells (dose-level 2, single [DL2S]).

 

Safety

 

More than 90% of patients experienced a treatment-emergent adverse event (AE), and 60% had a treatment-related AE.

 

Treatment-emergent AEs occurring in more than 20% of patients included cytokine release syndrome (CRS), fatigue, nausea, constipation, decreased appetite, diarrhea, hypotension, neutropenia, anemia, and thrombocytopenia.

 

One patient had a grade 5 AE of diffuse alveolar damage that was thought to be related to fludarabine, cyclophosphamide, and JCAR017.

 

Another patient had a grade 5 AE of multiorgan failure that was considered unrelated to study treatment and due to disease progression.

 

The rate of grade 1/2 CRS was 33% (n=18), and the rate of grade 3/4 CRS was 2% (n=1). The rate of grade 1/2 neurotoxicity was 6% (n=3), and the rate of grade 3/4 neurotoxicity was 16% (n=9).

 

There were no deaths from CRS or neurotoxicity. The median time to onset of CRS was 5 days (range, 1-23), and the median time to onset of neurotoxicity was 11 days (range, 5-23).

 

“JCAR017 toxicities have, thus far, been relatively low and highly manageable at all dose levels tested, with a favorable safety profile that may enable outpatient administration,” Dr Abramson said.

 

Response

 

Fifty-four patients were evaluable for response. The ORR was 76%, and the CR rate was 52%. At 3 months of follow-up, the ORR was 51%, and the CR rate was 39%.

 

Dr Abramson noted that there was a dose-response relationship.

 

Overall, in the DL1S cohort, the ORR was 80%, and the CR rate was 53%. In the DL2S cohort, the ORR was 72%, and the CR rate was 50%. In the DL1D cohort, the ORR was 67%, and the CR rate was 50%.

 

 

At 3 months, in the DL1S cohort, the ORR was 46%, and the CR rate was 33%. In the DL2S cohort, the ORR was 64%, and the CR rate was 46%. In the DL1D cohort, the ORR and CR rate were both 50%.

 

Dr Abramson also noted that JCAR017 could produce a high response rate in poor-risk subgroups.

 

At 3 months, the ORR was 91% in patients who relapsed less than 12 months after transplant, 82% in patients with double- or triple-hit lymphoma, 48% in patients who had never achieved a CR, 47% in chemo-refractory patients, 31% in patients with primary refractory lymphoma, and 24% in patients with stable disease or progression after last chemotherapy.

Photo by Rhoda Baer

MADRID—Patients with advanced Hodgkin lymphoma (HL) who are PET-negative after initial treatment with 2 cycles of eBEACOPP* should only receive 2 additional cycles of the therapy, new research suggests.

In the HD18 trial, PET-2-negative patients who received 4 cycles of eBEACOPP had non-inferior progression-free survival (PFS) and significantly better overall survival (OS) than PET-2-negative patients who received 6 or 8 cycles of the treatment.

Patients who received 4 cycles also had less severe toxicity and fewer second neoplasms than patients who received more cycles of eBEACOPP.

“When balancing efficacy and safety, results compare favorably with any other published treatment strategy so far,” said Peter Borchmann, MD, of University Hospital of Cologne in Germany.

“That’s why we recommend treatment with PET-2-guided eBEACOPP for patients with newly diagnosed, advanced-stage Hodgkin lymphoma.”

Dr Borchmann presented results from HD18 at the 22nd Congress of the European Hematology Association (EHA) as abstract S150.

Patients and treatment

Dr Borchmann and his colleagues set out to determine if they could decrease the number of eBEACOPP cycles in patients with negative PET-2 without compromising treatment efficacy.

From May 2008 to July 2014, the researchers recruited 2101 patients with newly diagnosed, advanced-stage HL.

Patients who were PET-negative after 2 cycles of eBEACOPP (n=1005) were initially randomized to receive 6 additional cycles of eBEACOPP or 2 additional cycles—a total of 8 cycles or 4 cycles, respectively. The protocol was later amended (in June 2011), and the total number of cycles in the standard therapy arm was reduced to 6.

There were 504 patients in the standard therapy arm—288 who received 8 cycles of eBEACOPP and 216 who received 6 cycles. There were 501 patients who received 4 cycles of eBEACOPP.

Sixteen patients in the standard therapy arm and 17 in the 4-cycle arm also received radiotherapy.

The median age was 32 (range, 18-60) in the standard therapy arm and 33 (range, 18-60) in the 4-cycle arm. Sixty-three percent and 62% of patients, respectively, were male.

Eight percent of patients in both arms had Ann Arbor stage IIB disease. Fifty-seven percent in the standard therapy arm and 55% in the 4-cycle arm had stage IIIA/B. And 35% and 36%, respectively, had stage IVA/B disease.

Thirty-five percent of patients in both arms had an IPS stage of 0-1. Fifty-one percent in the standard therapy arm and 52% in the 4-cycle arm had an IPS stage of 2-3. And 14% in both arms had an IPS stage of 4-7.

The median duration of therapy was 173 days (range, 41-266) for patients randomized to receive 8 cycles of eBEACOPP, 129 days (range, 35-178) in patients randomized to receive 6 cycles, and 85 days (range, 42-133) in patients randomized to receive 4 cycles.

One patient in the 6-cycle group received more than 6 cycles, and 6 patients in the 4-cycle arm received more than 4 cycles.

PFS and OS

The median follow-up was 55 months. The estimated 3-year PFS was 92.3% in the standard therapy arm and 94.8% in the 4-cycle arm. The estimated 5-year PFS was 91.2% and 91.8%, respectively. The hazard ratio was 0.88.

“[Based on these data,] we can conclude that 4 cycles are as effective as 6 or 8 cycles,” Dr Borchmann said.

The estimated 3-year OS was 95.9% in the standard therapy arm and 98.7% in the 4-cycle arm. The estimated 5-year OS was 95.4% and 97.6%, respectively. The hazard ratio was 0.36 (P=0.006).

Toxicity and second neoplasms

 

Grade 3/4 organ toxicity occurred in 22% of patients in the 8-cycle group, 13% in the 6-cycle group, and 8% in the 4-cycle group. Grade 4 anemia, thrombocytopenia, or infection occurred in 59%, 53%, and 38%, respectively.

Treatment-related morbidity occurred in 66% of patients in the 8-cycle group, 61% in the 6-cycle group, and 41% in the 4-cycle group.

Eighteen patients in the standard therapy arm had second neoplasms—8 with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 5 with non-Hodgkin lymphoma (NHL), and 5 with solid tumors.

Thirteen patients in the 4-cycle arm had second neoplasms—2 with AML/MDS, 8 with NHL, and 3 with solid tumors.

Causes of death

The cause of death was HL for 0.6% of patients (n=3) in the standard therapy arm and for 0.8% of patients (n=4) in the 4-cycle arm.

The cause of death was second malignancy for 2.2% of patients (n=11) in the standard therapy arm. Five patients died of AML, 3 of NHL, and 3 of solid tumor malignancies.

One patient (0.2%) in the 4-cycle arm died as a result of a second malignancy, which was AML.

Toxicity related to study treatment was the cause of death for 1.2% (n=6) of patients in the standard therapy arm. Five of the patients died of infection, and the sixth died of ischemic stroke.

None of the patients in the 4-cycle arm died of toxicity related to study treatment.

Other causes of death included toxicity of salvage treatment (0.4%, n=2 in both arms), other disease (0.2%, n=1 in both arms), accident (1 patient [0.2%] in the 4-cycle arm), and unknown cause (2 patients [0.4%] in the standard arm).

“[With 4 cycles of therapy,] we had a significant and very relevant reduction of severe, acute hematological and non-hematological toxicities, and this was accompanied by a relevant reduction of mortality for other reasons than HL,” Dr Borchmann said. “And we’ve almost eliminated HL as a cause of death in this trial.” 

*dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone

Photo by Rhoda Baer

MADRID—Patients with advanced Hodgkin lymphoma (HL) who are PET-negative after initial treatment with 2 cycles of eBEACOPP* should only receive 2 additional cycles of the therapy, new research suggests.

In the HD18 trial, PET-2-negative patients who received 4 cycles of eBEACOPP had non-inferior progression-free survival (PFS) and significantly better overall survival (OS) than PET-2-negative patients who received 6 or 8 cycles of the treatment.

Patients who received 4 cycles also had less severe toxicity and fewer second neoplasms than patients who received more cycles of eBEACOPP.

“When balancing efficacy and safety, results compare favorably with any other published treatment strategy so far,” said Peter Borchmann, MD, of University Hospital of Cologne in Germany.

“That’s why we recommend treatment with PET-2-guided eBEACOPP for patients with newly diagnosed, advanced-stage Hodgkin lymphoma.”

Dr Borchmann presented results from HD18 at the 22nd Congress of the European Hematology Association (EHA) as abstract S150.

Patients and treatment

Dr Borchmann and his colleagues set out to determine if they could decrease the number of eBEACOPP cycles in patients with negative PET-2 without compromising treatment efficacy.

From May 2008 to July 2014, the researchers recruited 2101 patients with newly diagnosed, advanced-stage HL.

Patients who were PET-negative after 2 cycles of eBEACOPP (n=1005) were initially randomized to receive 6 additional cycles of eBEACOPP or 2 additional cycles—a total of 8 cycles or 4 cycles, respectively. The protocol was later amended (in June 2011), and the total number of cycles in the standard therapy arm was reduced to 6.

There were 504 patients in the standard therapy arm—288 who received 8 cycles of eBEACOPP and 216 who received 6 cycles. There were 501 patients who received 4 cycles of eBEACOPP.

Sixteen patients in the standard therapy arm and 17 in the 4-cycle arm also received radiotherapy.

The median age was 32 (range, 18-60) in the standard therapy arm and 33 (range, 18-60) in the 4-cycle arm. Sixty-three percent and 62% of patients, respectively, were male.

Eight percent of patients in both arms had Ann Arbor stage IIB disease. Fifty-seven percent in the standard therapy arm and 55% in the 4-cycle arm had stage IIIA/B. And 35% and 36%, respectively, had stage IVA/B disease.

Thirty-five percent of patients in both arms had an IPS stage of 0-1. Fifty-one percent in the standard therapy arm and 52% in the 4-cycle arm had an IPS stage of 2-3. And 14% in both arms had an IPS stage of 4-7.

The median duration of therapy was 173 days (range, 41-266) for patients randomized to receive 8 cycles of eBEACOPP, 129 days (range, 35-178) in patients randomized to receive 6 cycles, and 85 days (range, 42-133) in patients randomized to receive 4 cycles.

One patient in the 6-cycle group received more than 6 cycles, and 6 patients in the 4-cycle arm received more than 4 cycles.

PFS and OS

The median follow-up was 55 months. The estimated 3-year PFS was 92.3% in the standard therapy arm and 94.8% in the 4-cycle arm. The estimated 5-year PFS was 91.2% and 91.8%, respectively. The hazard ratio was 0.88.

“[Based on these data,] we can conclude that 4 cycles are as effective as 6 or 8 cycles,” Dr Borchmann said.

The estimated 3-year OS was 95.9% in the standard therapy arm and 98.7% in the 4-cycle arm. The estimated 5-year OS was 95.4% and 97.6%, respectively. The hazard ratio was 0.36 (P=0.006).

Toxicity and second neoplasms

 

Grade 3/4 organ toxicity occurred in 22% of patients in the 8-cycle group, 13% in the 6-cycle group, and 8% in the 4-cycle group. Grade 4 anemia, thrombocytopenia, or infection occurred in 59%, 53%, and 38%, respectively.

Treatment-related morbidity occurred in 66% of patients in the 8-cycle group, 61% in the 6-cycle group, and 41% in the 4-cycle group.

Eighteen patients in the standard therapy arm had second neoplasms—8 with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 5 with non-Hodgkin lymphoma (NHL), and 5 with solid tumors.

Thirteen patients in the 4-cycle arm had second neoplasms—2 with AML/MDS, 8 with NHL, and 3 with solid tumors.

Causes of death

The cause of death was HL for 0.6% of patients (n=3) in the standard therapy arm and for 0.8% of patients (n=4) in the 4-cycle arm.

The cause of death was second malignancy for 2.2% of patients (n=11) in the standard therapy arm. Five patients died of AML, 3 of NHL, and 3 of solid tumor malignancies.

One patient (0.2%) in the 4-cycle arm died as a result of a second malignancy, which was AML.

Toxicity related to study treatment was the cause of death for 1.2% (n=6) of patients in the standard therapy arm. Five of the patients died of infection, and the sixth died of ischemic stroke.

None of the patients in the 4-cycle arm died of toxicity related to study treatment.

Other causes of death included toxicity of salvage treatment (0.4%, n=2 in both arms), other disease (0.2%, n=1 in both arms), accident (1 patient [0.2%] in the 4-cycle arm), and unknown cause (2 patients [0.4%] in the standard arm).

“[With 4 cycles of therapy,] we had a significant and very relevant reduction of severe, acute hematological and non-hematological toxicities, and this was accompanied by a relevant reduction of mortality for other reasons than HL,” Dr Borchmann said. “And we’ve almost eliminated HL as a cause of death in this trial.” 

*dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone

Photo by Rhoda Baer

MADRID—Patients with advanced Hodgkin lymphoma (HL) who are PET-negative after initial treatment with 2 cycles of eBEACOPP* should only receive 2 additional cycles of the therapy, new research suggests.

In the HD18 trial, PET-2-negative patients who received 4 cycles of eBEACOPP had non-inferior progression-free survival (PFS) and significantly better overall survival (OS) than PET-2-negative patients who received 6 or 8 cycles of the treatment.

Patients who received 4 cycles also had less severe toxicity and fewer second neoplasms than patients who received more cycles of eBEACOPP.

“When balancing efficacy and safety, results compare favorably with any other published treatment strategy so far,” said Peter Borchmann, MD, of University Hospital of Cologne in Germany.

“That’s why we recommend treatment with PET-2-guided eBEACOPP for patients with newly diagnosed, advanced-stage Hodgkin lymphoma.”

Dr Borchmann presented results from HD18 at the 22nd Congress of the European Hematology Association (EHA) as abstract S150.

Patients and treatment

Dr Borchmann and his colleagues set out to determine if they could decrease the number of eBEACOPP cycles in patients with negative PET-2 without compromising treatment efficacy.

From May 2008 to July 2014, the researchers recruited 2101 patients with newly diagnosed, advanced-stage HL.

Patients who were PET-negative after 2 cycles of eBEACOPP (n=1005) were initially randomized to receive 6 additional cycles of eBEACOPP or 2 additional cycles—a total of 8 cycles or 4 cycles, respectively. The protocol was later amended (in June 2011), and the total number of cycles in the standard therapy arm was reduced to 6.

There were 504 patients in the standard therapy arm—288 who received 8 cycles of eBEACOPP and 216 who received 6 cycles. There were 501 patients who received 4 cycles of eBEACOPP.

Sixteen patients in the standard therapy arm and 17 in the 4-cycle arm also received radiotherapy.

The median age was 32 (range, 18-60) in the standard therapy arm and 33 (range, 18-60) in the 4-cycle arm. Sixty-three percent and 62% of patients, respectively, were male.

Eight percent of patients in both arms had Ann Arbor stage IIB disease. Fifty-seven percent in the standard therapy arm and 55% in the 4-cycle arm had stage IIIA/B. And 35% and 36%, respectively, had stage IVA/B disease.

Thirty-five percent of patients in both arms had an IPS stage of 0-1. Fifty-one percent in the standard therapy arm and 52% in the 4-cycle arm had an IPS stage of 2-3. And 14% in both arms had an IPS stage of 4-7.

The median duration of therapy was 173 days (range, 41-266) for patients randomized to receive 8 cycles of eBEACOPP, 129 days (range, 35-178) in patients randomized to receive 6 cycles, and 85 days (range, 42-133) in patients randomized to receive 4 cycles.

One patient in the 6-cycle group received more than 6 cycles, and 6 patients in the 4-cycle arm received more than 4 cycles.

PFS and OS

The median follow-up was 55 months. The estimated 3-year PFS was 92.3% in the standard therapy arm and 94.8% in the 4-cycle arm. The estimated 5-year PFS was 91.2% and 91.8%, respectively. The hazard ratio was 0.88.

“[Based on these data,] we can conclude that 4 cycles are as effective as 6 or 8 cycles,” Dr Borchmann said.

The estimated 3-year OS was 95.9% in the standard therapy arm and 98.7% in the 4-cycle arm. The estimated 5-year OS was 95.4% and 97.6%, respectively. The hazard ratio was 0.36 (P=0.006).

Toxicity and second neoplasms

 

Grade 3/4 organ toxicity occurred in 22% of patients in the 8-cycle group, 13% in the 6-cycle group, and 8% in the 4-cycle group. Grade 4 anemia, thrombocytopenia, or infection occurred in 59%, 53%, and 38%, respectively.

Treatment-related morbidity occurred in 66% of patients in the 8-cycle group, 61% in the 6-cycle group, and 41% in the 4-cycle group.

Eighteen patients in the standard therapy arm had second neoplasms—8 with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 5 with non-Hodgkin lymphoma (NHL), and 5 with solid tumors.

Thirteen patients in the 4-cycle arm had second neoplasms—2 with AML/MDS, 8 with NHL, and 3 with solid tumors.

Causes of death

The cause of death was HL for 0.6% of patients (n=3) in the standard therapy arm and for 0.8% of patients (n=4) in the 4-cycle arm.

The cause of death was second malignancy for 2.2% of patients (n=11) in the standard therapy arm. Five patients died of AML, 3 of NHL, and 3 of solid tumor malignancies.

One patient (0.2%) in the 4-cycle arm died as a result of a second malignancy, which was AML.

Toxicity related to study treatment was the cause of death for 1.2% (n=6) of patients in the standard therapy arm. Five of the patients died of infection, and the sixth died of ischemic stroke.

None of the patients in the 4-cycle arm died of toxicity related to study treatment.

Other causes of death included toxicity of salvage treatment (0.4%, n=2 in both arms), other disease (0.2%, n=1 in both arms), accident (1 patient [0.2%] in the 4-cycle arm), and unknown cause (2 patients [0.4%] in the standard arm).

“[With 4 cycles of therapy,] we had a significant and very relevant reduction of severe, acute hematological and non-hematological toxicities, and this was accompanied by a relevant reduction of mortality for other reasons than HL,” Dr Borchmann said. “And we’ve almost eliminated HL as a cause of death in this trial.” 

*dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone

Photo courtesy of Columbia University

A small retrospective study of survivors of childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) has found that phosphorylated Tau (p-Tau) in patients’ cerebrospinal fluid (CSF) is a predictor of late neurocognitive consequences.

Investigators compared intellectual performance, memory, and executive functioning between survivors and control subjects and observed that CSF levels of p-Tau during treatment and total intrathecal methotrexate dose negatively correlated with intellectual performance.

They suggest that identifying at-risk children early “could inspire interventions to prevent or remediate chemotherapy-induced cognitive sequelae.”

The investigators enrolled 31 nonirradiated adults, 27 who had had ALL and 4 NHL. They compared the survivors to 35 age-matched controls.

All study participants were a mean age of 21.5 years (range, 16.1–29.8). The mean age of the survivors at diagnosis was 6.4 years.

"Our team collected samples of brain fluid during the cancer treatment,” Rudi D’Hooge, PhD, of KU Leuven in Belgium, said. “We analyzed the p-Tau levels to measure the damage to the brain cells."

Investigators assessed intelligence, memory, and executive function using Wechsler Adult Intelligence Scale (WAIS IV), Rey Auditory Verbal Learning Test (AVLT), and Amsterdam Neuropsychological Tasks (ANT), respectively.

Statistical analysis included two-sided, one-way analysis of covariance (ANCOVA) with survivor group vs control group as an independent factor.  Parental socioeconomic status was a covariate.

Dr D’Hooge and colleagues published their findings in JNCI, the Journal of the National Cancer Institute.

Findings

Investigators found that survivors had statistically significant lower total intelligence (P=0.001), verbal intelligence (P=0.02), and performance intelligence (P=0.007) quotients than controls.

They also found a negative correlation between CSF p-Tau, but not CSF Tau, levels and total intelligence (P=0.02), verbal intelligence (P=0.001), and performance intelligence (P=0.04) quotients.

Only performance intelligence was negatively correlated with total intrathecal methotrexate (P=0.007).

And because total intrathecal methotrexate dose and CSF p-Tau were not significantly correlated (P=0.29), the investigators believe intervening factors increase CSF p-Tau independently from methotrexate dose.

Results of subset tests revealed that cognitive flexibility (set-shifting and working memory), and processing speed were affected (P<0.05).

However, long-term memory, focused and sustained attention, and inhibition appeared unaffected (P>0.05).

The investigators believe these differences in vulnerability of cognitive functions parallel patient age at time of development.

For example, long-term memory, focused and sustained attention, and inhibition develop before children reach 6 years, the mean age at which the survivor cohort was diagnosed.

But set-shifting, working memory, and processing speed mature during adolescence, after the patients were diagnosed and treated.

Limitations of the study, according to the investigators, include its retrospective and cross-sectional design, the relatively small sample size, and the lack of pretreatment neurocognitive data.

Nevertheless, they believe the study should encourage the use of the CSF biomarker, intrathecal methotrexate dose, and age at therapy initiation in neurotoxicity assessments to identify children at risk for long-term sequelae.

"If we systematically measure these p-Tau levels in the future," Iris Elens, MD, also of KU Leuven, said, "we can offer specific help to children with high values. With early coaching aimed at the most relevant functions we can prevent problems that would otherwise manifest 10 to 15 years after the treatment."

The Olivia Hendrickx Research Fund supported the study. 

Photo courtesy of Columbia University

A small retrospective study of survivors of childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) has found that phosphorylated Tau (p-Tau) in patients’ cerebrospinal fluid (CSF) is a predictor of late neurocognitive consequences.

Investigators compared intellectual performance, memory, and executive functioning between survivors and control subjects and observed that CSF levels of p-Tau during treatment and total intrathecal methotrexate dose negatively correlated with intellectual performance.

They suggest that identifying at-risk children early “could inspire interventions to prevent or remediate chemotherapy-induced cognitive sequelae.”

The investigators enrolled 31 nonirradiated adults, 27 who had had ALL and 4 NHL. They compared the survivors to 35 age-matched controls.

All study participants were a mean age of 21.5 years (range, 16.1–29.8). The mean age of the survivors at diagnosis was 6.4 years.

"Our team collected samples of brain fluid during the cancer treatment,” Rudi D’Hooge, PhD, of KU Leuven in Belgium, said. “We analyzed the p-Tau levels to measure the damage to the brain cells."

Investigators assessed intelligence, memory, and executive function using Wechsler Adult Intelligence Scale (WAIS IV), Rey Auditory Verbal Learning Test (AVLT), and Amsterdam Neuropsychological Tasks (ANT), respectively.

Statistical analysis included two-sided, one-way analysis of covariance (ANCOVA) with survivor group vs control group as an independent factor.  Parental socioeconomic status was a covariate.

Dr D’Hooge and colleagues published their findings in JNCI, the Journal of the National Cancer Institute.

Findings

Investigators found that survivors had statistically significant lower total intelligence (P=0.001), verbal intelligence (P=0.02), and performance intelligence (P=0.007) quotients than controls.

They also found a negative correlation between CSF p-Tau, but not CSF Tau, levels and total intelligence (P=0.02), verbal intelligence (P=0.001), and performance intelligence (P=0.04) quotients.

Only performance intelligence was negatively correlated with total intrathecal methotrexate (P=0.007).

And because total intrathecal methotrexate dose and CSF p-Tau were not significantly correlated (P=0.29), the investigators believe intervening factors increase CSF p-Tau independently from methotrexate dose.

Results of subset tests revealed that cognitive flexibility (set-shifting and working memory), and processing speed were affected (P<0.05).

However, long-term memory, focused and sustained attention, and inhibition appeared unaffected (P>0.05).

The investigators believe these differences in vulnerability of cognitive functions parallel patient age at time of development.

For example, long-term memory, focused and sustained attention, and inhibition develop before children reach 6 years, the mean age at which the survivor cohort was diagnosed.

But set-shifting, working memory, and processing speed mature during adolescence, after the patients were diagnosed and treated.

Limitations of the study, according to the investigators, include its retrospective and cross-sectional design, the relatively small sample size, and the lack of pretreatment neurocognitive data.

Nevertheless, they believe the study should encourage the use of the CSF biomarker, intrathecal methotrexate dose, and age at therapy initiation in neurotoxicity assessments to identify children at risk for long-term sequelae.

"If we systematically measure these p-Tau levels in the future," Iris Elens, MD, also of KU Leuven, said, "we can offer specific help to children with high values. With early coaching aimed at the most relevant functions we can prevent problems that would otherwise manifest 10 to 15 years after the treatment."

The Olivia Hendrickx Research Fund supported the study. 

Photo courtesy of Columbia University

A small retrospective study of survivors of childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL) has found that phosphorylated Tau (p-Tau) in patients’ cerebrospinal fluid (CSF) is a predictor of late neurocognitive consequences.

Investigators compared intellectual performance, memory, and executive functioning between survivors and control subjects and observed that CSF levels of p-Tau during treatment and total intrathecal methotrexate dose negatively correlated with intellectual performance.

They suggest that identifying at-risk children early “could inspire interventions to prevent or remediate chemotherapy-induced cognitive sequelae.”

The investigators enrolled 31 nonirradiated adults, 27 who had had ALL and 4 NHL. They compared the survivors to 35 age-matched controls.

All study participants were a mean age of 21.5 years (range, 16.1–29.8). The mean age of the survivors at diagnosis was 6.4 years.

"Our team collected samples of brain fluid during the cancer treatment,” Rudi D’Hooge, PhD, of KU Leuven in Belgium, said. “We analyzed the p-Tau levels to measure the damage to the brain cells."

Investigators assessed intelligence, memory, and executive function using Wechsler Adult Intelligence Scale (WAIS IV), Rey Auditory Verbal Learning Test (AVLT), and Amsterdam Neuropsychological Tasks (ANT), respectively.

Statistical analysis included two-sided, one-way analysis of covariance (ANCOVA) with survivor group vs control group as an independent factor.  Parental socioeconomic status was a covariate.

Dr D’Hooge and colleagues published their findings in JNCI, the Journal of the National Cancer Institute.

Findings

Investigators found that survivors had statistically significant lower total intelligence (P=0.001), verbal intelligence (P=0.02), and performance intelligence (P=0.007) quotients than controls.

They also found a negative correlation between CSF p-Tau, but not CSF Tau, levels and total intelligence (P=0.02), verbal intelligence (P=0.001), and performance intelligence (P=0.04) quotients.

Only performance intelligence was negatively correlated with total intrathecal methotrexate (P=0.007).

And because total intrathecal methotrexate dose and CSF p-Tau were not significantly correlated (P=0.29), the investigators believe intervening factors increase CSF p-Tau independently from methotrexate dose.

Results of subset tests revealed that cognitive flexibility (set-shifting and working memory), and processing speed were affected (P<0.05).

However, long-term memory, focused and sustained attention, and inhibition appeared unaffected (P>0.05).

The investigators believe these differences in vulnerability of cognitive functions parallel patient age at time of development.

For example, long-term memory, focused and sustained attention, and inhibition develop before children reach 6 years, the mean age at which the survivor cohort was diagnosed.

But set-shifting, working memory, and processing speed mature during adolescence, after the patients were diagnosed and treated.

Limitations of the study, according to the investigators, include its retrospective and cross-sectional design, the relatively small sample size, and the lack of pretreatment neurocognitive data.

Nevertheless, they believe the study should encourage the use of the CSF biomarker, intrathecal methotrexate dose, and age at therapy initiation in neurotoxicity assessments to identify children at risk for long-term sequelae.

"If we systematically measure these p-Tau levels in the future," Iris Elens, MD, also of KU Leuven, said, "we can offer specific help to children with high values. With early coaching aimed at the most relevant functions we can prevent problems that would otherwise manifest 10 to 15 years after the treatment."

The Olivia Hendrickx Research Fund supported the study. 

Micrograph showing HL

Brentuximab vedotin (Adcetris®) in combination with a 3-drug chemotherapy regimen has met its primary endpoint of statistically significant improvement in modified progression-free survival (mPFS) compared with standard therapy in frontline treatment of advanced stage Hodgkin lymphoma (HL).

The ECHELON-1 trial tested brentuximab vedotin plus Adriamycin, vinblastine, and dacarbazine (AVD) against Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) in 1334 patients with previously untreated advanced HL.

Patients treated with brentuximab showed an 82% lower risk of disease progression compared with 77% in the ABVD arm.

Brentuximab vedotin is currently not approved as a frontline therapy for HL.

“Notably, this is the first clinical trial in frontline advanced Hodgkin lymphoma to show superior efficacy of a regimen that eliminates bleomycin,” said Clay Siegall, PhD, president and CEO of Seattle Genetics.

Dirk Huebner, MD, executive medical director of oncology at Takeda Pharmaceutical Company, said the results of the trial “have the potential to change the treatment approach of frontline advanced Hodgkin lymphoma.”

Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Seattle Genetics has US and Canadian commercialization rights and Takeda has rights to commercialize it in the rest of the world.

Brentuximab vedotin is an antibody-drug conjugate (ADC) made up of an anti-CD30 monoclonal antibody attached by a linker to monomethyl auristatin E (MMAE). The linker system is stable in the bloodstream but releases MMAE when internalized into CD30-expressing tumor cells.

ECHELON-1

ECHELON-1 (NCT01712490) is a randomized, 2-arm, multicenter phase 3 trial comparing brentuximab vedotin plus AVD to ABVD as frontline therapy in treatment-naïve advanced HL.

The trial enrolled 1334 patients with histologically confirmed advanced HL.

The primary endpoint is mPFS by independent review facility.

The investigators, regulatory bodies, and trial sponsors defined mPFS as the time to progression, death, or receipt of additional anticancer therapy for patients who were not in complete response (CR) after completion of frontline therapy.

They chose mPFS instead of PFS because they say it provides a clearer picture of the efficacy of primary anticancer therapy by eliminating the confounding effects of additional anticancer therapy.

Secondary endpoints include overall survival (OS), CR, and safety.

The results demonstrated that combination treatment with brentuximab resulted in a statistically significant improvement in mPFS versus the control arm (hazard ratio=0.770; P=0.035).

Interim analysis of OS, the key secondary endpoint, also trended in favor of the brentuximab plus AVD arm.

The safety profile of the brentuximab combination was consistent with that of the single-agent components of the regimen.

Patients in the brentuximab arm experienced an increased incidence of febrile neutropenia and peripheral neuropathy compared to the ABVD arm.

Febrile neutropenia was reduced with the use of prophylactic growth factors.

Peripheral neuropathy was managed through dose modifications.

Patients treated with ABVD had an increased rate and severity of pulmonary toxicity.

The companies plan to submit an abstract for presentation at the American Society of Hematology annual meeting in December.

Brentuximab is currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with classical HL who have received a prior stem cell transplant or 2 prior chemotherapy treatments.

Brentuximab is also approved to treat patient with anaplastic large cell lymphoma who have failed one prior treatment.

For more on brentuximab vedotin, see the full prescribing informtion. 

Micrograph showing HL

Brentuximab vedotin (Adcetris®) in combination with a 3-drug chemotherapy regimen has met its primary endpoint of statistically significant improvement in modified progression-free survival (mPFS) compared with standard therapy in frontline treatment of advanced stage Hodgkin lymphoma (HL).

The ECHELON-1 trial tested brentuximab vedotin plus Adriamycin, vinblastine, and dacarbazine (AVD) against Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) in 1334 patients with previously untreated advanced HL.

Patients treated with brentuximab showed an 82% lower risk of disease progression compared with 77% in the ABVD arm.

Brentuximab vedotin is currently not approved as a frontline therapy for HL.

“Notably, this is the first clinical trial in frontline advanced Hodgkin lymphoma to show superior efficacy of a regimen that eliminates bleomycin,” said Clay Siegall, PhD, president and CEO of Seattle Genetics.

Dirk Huebner, MD, executive medical director of oncology at Takeda Pharmaceutical Company, said the results of the trial “have the potential to change the treatment approach of frontline advanced Hodgkin lymphoma.”

Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Seattle Genetics has US and Canadian commercialization rights and Takeda has rights to commercialize it in the rest of the world.

Brentuximab vedotin is an antibody-drug conjugate (ADC) made up of an anti-CD30 monoclonal antibody attached by a linker to monomethyl auristatin E (MMAE). The linker system is stable in the bloodstream but releases MMAE when internalized into CD30-expressing tumor cells.

ECHELON-1

ECHELON-1 (NCT01712490) is a randomized, 2-arm, multicenter phase 3 trial comparing brentuximab vedotin plus AVD to ABVD as frontline therapy in treatment-naïve advanced HL.

The trial enrolled 1334 patients with histologically confirmed advanced HL.

The primary endpoint is mPFS by independent review facility.

The investigators, regulatory bodies, and trial sponsors defined mPFS as the time to progression, death, or receipt of additional anticancer therapy for patients who were not in complete response (CR) after completion of frontline therapy.

They chose mPFS instead of PFS because they say it provides a clearer picture of the efficacy of primary anticancer therapy by eliminating the confounding effects of additional anticancer therapy.

Secondary endpoints include overall survival (OS), CR, and safety.

The results demonstrated that combination treatment with brentuximab resulted in a statistically significant improvement in mPFS versus the control arm (hazard ratio=0.770; P=0.035).

Interim analysis of OS, the key secondary endpoint, also trended in favor of the brentuximab plus AVD arm.

The safety profile of the brentuximab combination was consistent with that of the single-agent components of the regimen.

Patients in the brentuximab arm experienced an increased incidence of febrile neutropenia and peripheral neuropathy compared to the ABVD arm.

Febrile neutropenia was reduced with the use of prophylactic growth factors.

Peripheral neuropathy was managed through dose modifications.

Patients treated with ABVD had an increased rate and severity of pulmonary toxicity.

The companies plan to submit an abstract for presentation at the American Society of Hematology annual meeting in December.

Brentuximab is currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with classical HL who have received a prior stem cell transplant or 2 prior chemotherapy treatments.

Brentuximab is also approved to treat patient with anaplastic large cell lymphoma who have failed one prior treatment.

For more on brentuximab vedotin, see the full prescribing informtion. 

Micrograph showing HL

Brentuximab vedotin (Adcetris®) in combination with a 3-drug chemotherapy regimen has met its primary endpoint of statistically significant improvement in modified progression-free survival (mPFS) compared with standard therapy in frontline treatment of advanced stage Hodgkin lymphoma (HL).

The ECHELON-1 trial tested brentuximab vedotin plus Adriamycin, vinblastine, and dacarbazine (AVD) against Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) in 1334 patients with previously untreated advanced HL.

Patients treated with brentuximab showed an 82% lower risk of disease progression compared with 77% in the ABVD arm.

Brentuximab vedotin is currently not approved as a frontline therapy for HL.

“Notably, this is the first clinical trial in frontline advanced Hodgkin lymphoma to show superior efficacy of a regimen that eliminates bleomycin,” said Clay Siegall, PhD, president and CEO of Seattle Genetics.

Dirk Huebner, MD, executive medical director of oncology at Takeda Pharmaceutical Company, said the results of the trial “have the potential to change the treatment approach of frontline advanced Hodgkin lymphoma.”

Seattle Genetics and Takeda are jointly developing brentuximab vedotin. Seattle Genetics has US and Canadian commercialization rights and Takeda has rights to commercialize it in the rest of the world.

Brentuximab vedotin is an antibody-drug conjugate (ADC) made up of an anti-CD30 monoclonal antibody attached by a linker to monomethyl auristatin E (MMAE). The linker system is stable in the bloodstream but releases MMAE when internalized into CD30-expressing tumor cells.

ECHELON-1

ECHELON-1 (NCT01712490) is a randomized, 2-arm, multicenter phase 3 trial comparing brentuximab vedotin plus AVD to ABVD as frontline therapy in treatment-naïve advanced HL.

The trial enrolled 1334 patients with histologically confirmed advanced HL.

The primary endpoint is mPFS by independent review facility.

The investigators, regulatory bodies, and trial sponsors defined mPFS as the time to progression, death, or receipt of additional anticancer therapy for patients who were not in complete response (CR) after completion of frontline therapy.

They chose mPFS instead of PFS because they say it provides a clearer picture of the efficacy of primary anticancer therapy by eliminating the confounding effects of additional anticancer therapy.

Secondary endpoints include overall survival (OS), CR, and safety.

The results demonstrated that combination treatment with brentuximab resulted in a statistically significant improvement in mPFS versus the control arm (hazard ratio=0.770; P=0.035).

Interim analysis of OS, the key secondary endpoint, also trended in favor of the brentuximab plus AVD arm.

The safety profile of the brentuximab combination was consistent with that of the single-agent components of the regimen.

Patients in the brentuximab arm experienced an increased incidence of febrile neutropenia and peripheral neuropathy compared to the ABVD arm.

Febrile neutropenia was reduced with the use of prophylactic growth factors.

Peripheral neuropathy was managed through dose modifications.

Patients treated with ABVD had an increased rate and severity of pulmonary toxicity.

The companies plan to submit an abstract for presentation at the American Society of Hematology annual meeting in December.

Brentuximab is currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with classical HL who have received a prior stem cell transplant or 2 prior chemotherapy treatments.

Brentuximab is also approved to treat patient with anaplastic large cell lymphoma who have failed one prior treatment.

For more on brentuximab vedotin, see the full prescribing informtion. 

 

Syringe

 

The US Food and Drug Administration (FDA) approved a new, subcutaneous (SC) formulation of rituximab with hyaluronidase human (Rituxan Hycela™).

 

The new formulation includes the same monoclonal antibody as intravenous rituximab, but is combined with an enzyme that helps to deliver rituximab under the skin.

 

The new treatment reduces administration time from 1.5 hours or more for intravenous rituximab to 5 to 7 minutes for the subcutaneous injection.

 

It is approved for use in adults with previously untreated and relapsed or refractory follicular lymphoma (FL), previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL).

 

“[P]eople with 3 of the most common blood cancers now have a new treatment option which provides efficacy comparable with intravenous Rituxan and can be delivered under the skin in minutes instead of hours through IV infusion,” said Sandra Horning, MD, chief medical officer of Genentech.

 

Rituxan Hycela is manufactured by Genentech, Inc, a member of the Roche Group, and jointly marketed by Biogen and Genentech USA, Inc.

 

“People who benefit from Rituxan may receive years of repeated treatments for their blood cancer, so an option that reduces the administration time can be important,” she noted.

 

The FDA based its decision on results from 4 clinical studies:

 

 

 

 

 

 

• SABRINA (NCT01200758): Phase 3 combination study with chemotherapy and maintenance study in previously untreated FL
• SAWYER (NCT01292603): Phase 1b study in previously untreated CLL
• MabEase (NCT01649856): Phase 3 study in previously untreated DLBCL
• PrefMab (NCT01724021): Phase 3 patient preference study in previously untreated FL and DLBCL

This last study showed that 77% of patients preferred subcutaneous over intravenous administration, primarily because it reduced administration time.

 

Together, these trials represented nearly 2,000 people and demonstrated that subcutaneous administration of rituximab/hyaluronidase resulted in non-inferior levels of rituximab in the blood compared to intravenous rituximab.

 

And the subcutaneous formulation also demonstrated comparable clinical efficacy outcomes to the intravenous formulation.

 

Patients must have had at least 1 full dose of intravenous rituximab without severe adverse reactions before receiving the subcutaneous injection. There is a higher risk of certain severe adverse reactions during the first infusion.

 

The safety profile of rituximab/hyaluronidase is also comparable to intravenous rituximab, except for cutaneous reactions.

 

The most common (≥20%) adverse reactions observed with rituximab/hyaluronidase were:

 

 

 

 

 

• In FL, infections, neutropenia, nausea, constipation, cough, and fatigue.
• In DLBCL, infections, neutropenia, alopecia, nausea, and anemia.
• In CLL, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and erythema at the injection site.

Rituxan Hycela will be available in the US within 1 to 2 weeks, according to the manufacturer. Intravenous rituximab will continue to be available.

 

A subcutaneous formulation of rituximab (MabThera) had previously been approved for use in European markets by the European Commission.

 

For further information on the new US formulation, see the full prescribing information. 

 

 

 

Syringe

 

The US Food and Drug Administration (FDA) approved a new, subcutaneous (SC) formulation of rituximab with hyaluronidase human (Rituxan Hycela™).

 

The new formulation includes the same monoclonal antibody as intravenous rituximab, but is combined with an enzyme that helps to deliver rituximab under the skin.

 

The new treatment reduces administration time from 1.5 hours or more for intravenous rituximab to 5 to 7 minutes for the subcutaneous injection.

 

It is approved for use in adults with previously untreated and relapsed or refractory follicular lymphoma (FL), previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL).

 

“[P]eople with 3 of the most common blood cancers now have a new treatment option which provides efficacy comparable with intravenous Rituxan and can be delivered under the skin in minutes instead of hours through IV infusion,” said Sandra Horning, MD, chief medical officer of Genentech.

 

Rituxan Hycela is manufactured by Genentech, Inc, a member of the Roche Group, and jointly marketed by Biogen and Genentech USA, Inc.

 

“People who benefit from Rituxan may receive years of repeated treatments for their blood cancer, so an option that reduces the administration time can be important,” she noted.

 

The FDA based its decision on results from 4 clinical studies:

 

 

 

 

 

 

• SABRINA (NCT01200758): Phase 3 combination study with chemotherapy and maintenance study in previously untreated FL
• SAWYER (NCT01292603): Phase 1b study in previously untreated CLL
• MabEase (NCT01649856): Phase 3 study in previously untreated DLBCL
• PrefMab (NCT01724021): Phase 3 patient preference study in previously untreated FL and DLBCL

This last study showed that 77% of patients preferred subcutaneous over intravenous administration, primarily because it reduced administration time.

 

Together, these trials represented nearly 2,000 people and demonstrated that subcutaneous administration of rituximab/hyaluronidase resulted in non-inferior levels of rituximab in the blood compared to intravenous rituximab.

 

And the subcutaneous formulation also demonstrated comparable clinical efficacy outcomes to the intravenous formulation.

 

Patients must have had at least 1 full dose of intravenous rituximab without severe adverse reactions before receiving the subcutaneous injection. There is a higher risk of certain severe adverse reactions during the first infusion.

 

The safety profile of rituximab/hyaluronidase is also comparable to intravenous rituximab, except for cutaneous reactions.

 

The most common (≥20%) adverse reactions observed with rituximab/hyaluronidase were:

 

 

 

 

 

• In FL, infections, neutropenia, nausea, constipation, cough, and fatigue.
• In DLBCL, infections, neutropenia, alopecia, nausea, and anemia.
• In CLL, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and erythema at the injection site.

Rituxan Hycela will be available in the US within 1 to 2 weeks, according to the manufacturer. Intravenous rituximab will continue to be available.

 

A subcutaneous formulation of rituximab (MabThera) had previously been approved for use in European markets by the European Commission.

 

For further information on the new US formulation, see the full prescribing information. 

 

 

 

Syringe

 

The US Food and Drug Administration (FDA) approved a new, subcutaneous (SC) formulation of rituximab with hyaluronidase human (Rituxan Hycela™).

 

The new formulation includes the same monoclonal antibody as intravenous rituximab, but is combined with an enzyme that helps to deliver rituximab under the skin.

 

The new treatment reduces administration time from 1.5 hours or more for intravenous rituximab to 5 to 7 minutes for the subcutaneous injection.

 

It is approved for use in adults with previously untreated and relapsed or refractory follicular lymphoma (FL), previously untreated diffuse large B-cell lymphoma (DLBCL), and previously untreated and previously treated chronic lymphocytic leukemia (CLL).

 

“[P]eople with 3 of the most common blood cancers now have a new treatment option which provides efficacy comparable with intravenous Rituxan and can be delivered under the skin in minutes instead of hours through IV infusion,” said Sandra Horning, MD, chief medical officer of Genentech.

 

Rituxan Hycela is manufactured by Genentech, Inc, a member of the Roche Group, and jointly marketed by Biogen and Genentech USA, Inc.

 

“People who benefit from Rituxan may receive years of repeated treatments for their blood cancer, so an option that reduces the administration time can be important,” she noted.

 

The FDA based its decision on results from 4 clinical studies:

 

 

 

 

 

 

• SABRINA (NCT01200758): Phase 3 combination study with chemotherapy and maintenance study in previously untreated FL
• SAWYER (NCT01292603): Phase 1b study in previously untreated CLL
• MabEase (NCT01649856): Phase 3 study in previously untreated DLBCL
• PrefMab (NCT01724021): Phase 3 patient preference study in previously untreated FL and DLBCL

This last study showed that 77% of patients preferred subcutaneous over intravenous administration, primarily because it reduced administration time.

 

Together, these trials represented nearly 2,000 people and demonstrated that subcutaneous administration of rituximab/hyaluronidase resulted in non-inferior levels of rituximab in the blood compared to intravenous rituximab.

 

And the subcutaneous formulation also demonstrated comparable clinical efficacy outcomes to the intravenous formulation.

 

Patients must have had at least 1 full dose of intravenous rituximab without severe adverse reactions before receiving the subcutaneous injection. There is a higher risk of certain severe adverse reactions during the first infusion.

 

The safety profile of rituximab/hyaluronidase is also comparable to intravenous rituximab, except for cutaneous reactions.

 

The most common (≥20%) adverse reactions observed with rituximab/hyaluronidase were:

 

 

 

 

 

• In FL, infections, neutropenia, nausea, constipation, cough, and fatigue.
• In DLBCL, infections, neutropenia, alopecia, nausea, and anemia.
• In CLL, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and erythema at the injection site.

Rituxan Hycela will be available in the US within 1 to 2 weeks, according to the manufacturer. Intravenous rituximab will continue to be available.

 

A subcutaneous formulation of rituximab (MabThera) had previously been approved for use in European markets by the European Commission.

 

For further information on the new US formulation, see the full prescribing information. 

 

 

MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.

The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.

Cerdulatinib is an orally dosed agent that inhibits both the Janus kinase (JAK) 1 and 3 pathways and the spleen tyrosine kinase (SYK) pathway.

“At a dose of 30 mg b.i.d., cerdulatinib inhibited pathways of interest, so both SYK and JAK are inhibited at maximum amounts at physiologically attained doses,” he said at a briefing at the annual congress of the European Hematology Association.

Certain B cell malignancies are “addicted” to B cell antigen-receptor (BCR) signaling. A combination of selective SYK and JAK inhibitors can syngergistically suppress this response in B cell malignancies, he said.

In a phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL reported by Dr. Hamlin and his colleagues at the 2016 EHA annual congress, inhibition with cerdulatinib of both the BCR/SYK and JAK/STAT pathways in peripheral blood assays was well tolerated.

In the current phase II, multicenter, open-label study, the investigators plan on enrolling up to 40 patients in each of three cohorts: relapsed refractory CLL/SLL, relapsed/refractory indolent NHL, and relapsed diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed FL. The investigators have also begun to enroll patients with peripheral T-cell lymphoma (PTCL) based on efficacy of the dual pathway inhibitor against this malignancy.

The patients received 30-mg cerdulatinib orally twice daily until disease progression or intolerable toxicity.

As noted, the overall response rate was 50% (47 patients), including partial responses (PR) in 12 of 18 (67%) of patients with CLL/SLL, in five of nine patients (56%) with FL, and in one of seven patients with relapsed refractory marginal zone lymphoma and Waldenstrom macroglobulinemia.

In addition, the investigators identified one complete response in the first enrolled patient with PTCL.

“I think this is a proof of principle that the biology suggesting that SYK is expressed in T-cell lymphomas and may have an important role in its pathogenesis holds true,” Dr. Hamlin said.

Responses have been detected in heavily pretreated patients, including one patient with FL who had a relapse on ibrutinib and a patient with SLL who had a relapse during treatment with venetoclax. Both patients remain on cerdulatinib after 10 months. At the time of the data presentation, 15 patients are continuing therapy with the dual inhibitor, including 4 who have been taking it for more than 300 days.

The responses occurred after a median of two cycles, Dr. Hamlin noted, and improved over time, as seen in seven of nine patients with increased reduction of nodal masses at the second or third rescan.

The most frequent adverse events with cerdulatinib at the target dose of 30 mg are fatigue, diarrhea, nausea, and cytopenias.

In the dose-escalation phase, three patients at a dose of 35 mg b.i.d. had higher than expected drug concentrations and experienced severe adverse events, including two fatal infections and one grade 3 pancreatitis. The investigators launched a pharmacokinetics monitoring strategy in hopes of avoiding this complication in the future.

Dr. Hamlin said the efficacy to date suggests the cerdulatinib could be used as a single agent but added that its generally favorable safety profile may make it a good partner in combination therapies.

The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant role for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.

MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.

The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.

Cerdulatinib is an orally dosed agent that inhibits both the Janus kinase (JAK) 1 and 3 pathways and the spleen tyrosine kinase (SYK) pathway.

“At a dose of 30 mg b.i.d., cerdulatinib inhibited pathways of interest, so both SYK and JAK are inhibited at maximum amounts at physiologically attained doses,” he said at a briefing at the annual congress of the European Hematology Association.

Certain B cell malignancies are “addicted” to B cell antigen-receptor (BCR) signaling. A combination of selective SYK and JAK inhibitors can syngergistically suppress this response in B cell malignancies, he said.

In a phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL reported by Dr. Hamlin and his colleagues at the 2016 EHA annual congress, inhibition with cerdulatinib of both the BCR/SYK and JAK/STAT pathways in peripheral blood assays was well tolerated.

In the current phase II, multicenter, open-label study, the investigators plan on enrolling up to 40 patients in each of three cohorts: relapsed refractory CLL/SLL, relapsed/refractory indolent NHL, and relapsed diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed FL. The investigators have also begun to enroll patients with peripheral T-cell lymphoma (PTCL) based on efficacy of the dual pathway inhibitor against this malignancy.

The patients received 30-mg cerdulatinib orally twice daily until disease progression or intolerable toxicity.

As noted, the overall response rate was 50% (47 patients), including partial responses (PR) in 12 of 18 (67%) of patients with CLL/SLL, in five of nine patients (56%) with FL, and in one of seven patients with relapsed refractory marginal zone lymphoma and Waldenstrom macroglobulinemia.

In addition, the investigators identified one complete response in the first enrolled patient with PTCL.

“I think this is a proof of principle that the biology suggesting that SYK is expressed in T-cell lymphomas and may have an important role in its pathogenesis holds true,” Dr. Hamlin said.

Responses have been detected in heavily pretreated patients, including one patient with FL who had a relapse on ibrutinib and a patient with SLL who had a relapse during treatment with venetoclax. Both patients remain on cerdulatinib after 10 months. At the time of the data presentation, 15 patients are continuing therapy with the dual inhibitor, including 4 who have been taking it for more than 300 days.

The responses occurred after a median of two cycles, Dr. Hamlin noted, and improved over time, as seen in seven of nine patients with increased reduction of nodal masses at the second or third rescan.

The most frequent adverse events with cerdulatinib at the target dose of 30 mg are fatigue, diarrhea, nausea, and cytopenias.

In the dose-escalation phase, three patients at a dose of 35 mg b.i.d. had higher than expected drug concentrations and experienced severe adverse events, including two fatal infections and one grade 3 pancreatitis. The investigators launched a pharmacokinetics monitoring strategy in hopes of avoiding this complication in the future.

Dr. Hamlin said the efficacy to date suggests the cerdulatinib could be used as a single agent but added that its generally favorable safety profile may make it a good partner in combination therapies.

The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant role for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.

MADRID – Cerdulatinib, a single oral agent targeting two different pathways that lymphomas rely on for survival, produced rapid tumor responses in patients with relapsed or refractory non-Hodgkin lymphomas (NHL) in a phase II study.

The overall response rate among 47 patients enrolled in a phase II study was 50%, including responses among 67% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 56% of patients with follicular lymphoma (FL), reported Paul A. Hamlin, MD, of the Memorial Sloan Kettering Cancer Center in New York.

Cerdulatinib is an orally dosed agent that inhibits both the Janus kinase (JAK) 1 and 3 pathways and the spleen tyrosine kinase (SYK) pathway.

“At a dose of 30 mg b.i.d., cerdulatinib inhibited pathways of interest, so both SYK and JAK are inhibited at maximum amounts at physiologically attained doses,” he said at a briefing at the annual congress of the European Hematology Association.

Certain B cell malignancies are “addicted” to B cell antigen-receptor (BCR) signaling. A combination of selective SYK and JAK inhibitors can syngergistically suppress this response in B cell malignancies, he said.

In a phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL reported by Dr. Hamlin and his colleagues at the 2016 EHA annual congress, inhibition with cerdulatinib of both the BCR/SYK and JAK/STAT pathways in peripheral blood assays was well tolerated.

In the current phase II, multicenter, open-label study, the investigators plan on enrolling up to 40 patients in each of three cohorts: relapsed refractory CLL/SLL, relapsed/refractory indolent NHL, and relapsed diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and transformed FL. The investigators have also begun to enroll patients with peripheral T-cell lymphoma (PTCL) based on efficacy of the dual pathway inhibitor against this malignancy.

The patients received 30-mg cerdulatinib orally twice daily until disease progression or intolerable toxicity.

As noted, the overall response rate was 50% (47 patients), including partial responses (PR) in 12 of 18 (67%) of patients with CLL/SLL, in five of nine patients (56%) with FL, and in one of seven patients with relapsed refractory marginal zone lymphoma and Waldenstrom macroglobulinemia.

In addition, the investigators identified one complete response in the first enrolled patient with PTCL.

“I think this is a proof of principle that the biology suggesting that SYK is expressed in T-cell lymphomas and may have an important role in its pathogenesis holds true,” Dr. Hamlin said.

Responses have been detected in heavily pretreated patients, including one patient with FL who had a relapse on ibrutinib and a patient with SLL who had a relapse during treatment with venetoclax. Both patients remain on cerdulatinib after 10 months. At the time of the data presentation, 15 patients are continuing therapy with the dual inhibitor, including 4 who have been taking it for more than 300 days.

The responses occurred after a median of two cycles, Dr. Hamlin noted, and improved over time, as seen in seven of nine patients with increased reduction of nodal masses at the second or third rescan.

The most frequent adverse events with cerdulatinib at the target dose of 30 mg are fatigue, diarrhea, nausea, and cytopenias.

In the dose-escalation phase, three patients at a dose of 35 mg b.i.d. had higher than expected drug concentrations and experienced severe adverse events, including two fatal infections and one grade 3 pancreatitis. The investigators launched a pharmacokinetics monitoring strategy in hopes of avoiding this complication in the future.

Dr. Hamlin said the efficacy to date suggests the cerdulatinib could be used as a single agent but added that its generally favorable safety profile may make it a good partner in combination therapies.

The study is supported by Molecular Templates. Dr. Hamlin disclosed grant/research support and/or consultant role for Spectrum, GlaxoSmithKline, Pfizer, Seattle Genetics, Genentech, and Gilead.

 

Mantle cell lymphoma

 

LUGANO, SWITZERLAND—A chemotherapy-free combination regimen has demonstrated “favorable” safety and efficacy in patients with advanced chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and non-Hodgkin lymphoma (NHL), according to researchers.

 

They found that treatment with ublituximab, umbralisib, and ibrutinib produced responses in patients with CLL/SLL, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).

 

Many of these patients are still receiving the combination, some of them beyond 1 year, said Lorretta Nastoupil, MD, of MD Anderson Cancer Center in Houston, Texas.

 

She presented results with the treatment at the 14th International Conference on Malignant Lymphoma (ICML).

 

The research was sponsored by TG Therapeutics, the company developing ublituximab (TG-1101) and umbralisib (TGR-1202).

 

Patients and treatment

 

Dr Nastoupil presented data on 38 patients—20 with CLL/SLL, and 18 with NHL. Three of the CLL/SLL patients were treatment-naïve. The rest had relapsed/refractory disease.

 

All NHL patients had relapsed/refractory disease—6 with DLBCL, 6 with FL, 4 with MCL, and 2 with MZL.

 

For the entire cohort, the median age was 65 (range, 32-85), and most patients (n=29) were male. They had received a median of 3 prior treatment regimens (range, 0-6).

 

In this trial, the patients received:

 

 

 

 

 

• Ublituximab at 900 mg
• Ibrutinib at 420 mg (CLL/SLL) or 560 mg (NHL)
• Umbralisib at 400 mg, 600 mg, or 800 mg.

Eighty-one percent of patients have been on study for more than 6 months. The median time on study is 11.1 months (range, 0.4 to 30+ months).

 

Safety

 

There was 1 dose-limiting toxicity in the CLL cohort (umbralisib at 400 mg)—reactivated varicella zoster. And 2 patients discontinued treatment due to an adverse event (AE)—1 due to sepsis and 1 due to pneumonia.

 

Neutropenia (18%) and pneumonia (11%) were the only grade 3/4 AEs that occurred in more than 10% of patients. Other grade 3/4 AEs included thrombocytopenia (8%), diarrhea (3%), dizziness (3%), pyrexia (3%), rash (3%), anemia (3%), dyspnea (3%), and stomatitis (3%).

 

The most common AEs of any grade were diarrhea (47%), fatigue (47%), dizziness (37%), insomnia (34%), nausea (34%), neutropenia (32%), cough (32%), and infusion-related reactions (32%).

 

Efficacy

 

Thirty-six patients were evaluable for efficacy—19 with CLL/SLL and 17 with NHL patients. Two patients discontinued treatment before the first efficacy assessment—1 due to pneumonia and 1 at investigator discretion.

 

For the entire cohort, the overall response rate (ORR) was 83%.

 

In the CLL/SLL cohort, the ORR was 100% (19/19), and the complete response (CR) rate was 32% (n=6). However, 4 of the 6 CRs are pending bone marrow confirmation.

 

Dr Nastoupil noted that 8 of the CLL patients had a 17p and/or 11q deletion, and 3 had previously received treatment with a BTK and/or PI3Kδ inhibitor.

 

One patient who was refractory to both idelalisib and ibrutinib achieved a CR with the triplet regimen, and this response has been ongoing for more than 1.5 years.

 

Among patients with NHL, the ORR was 100% in patients with MZL (2/2) and MCL (4/4). The ORR was 80% (4/5) in FL patients, and 17% (1/6) in DLBCL patients.

 

The CR rate was 50% in patients with MZL (1/2) and MCL (2/4) and 20% in patients with FL (1/5).

 

Dr Nastoupil pointed out that the FL patients were heavily pretreated. Two of them had received an autologous stem cell transplant, 1 was refractory to prior ibrutinib treatment, and 1 had received 5 prior lines of rituximab-based therapy.

 

She also noted that the DLBCL patients had a median of 4 prior therapies, and 4 of these patients had non-GCB DLBCL, including the only patient who responded to the triplet.

 

 

“[T]he combination of ublituximab, umbralisib, and ibrutinib in advanced CLL and NHL demonstrated a favorable toxicity profile as well as favorable efficacy,” Dr Nastoupil said in closing.

 

“[This] suggests umbralisib may be safely combined with other targeted agents to overcome mechanisms of resistance.” 

 

Mantle cell lymphoma

 

LUGANO, SWITZERLAND—A chemotherapy-free combination regimen has demonstrated “favorable” safety and efficacy in patients with advanced chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and non-Hodgkin lymphoma (NHL), according to researchers.

 

They found that treatment with ublituximab, umbralisib, and ibrutinib produced responses in patients with CLL/SLL, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).

 

Many of these patients are still receiving the combination, some of them beyond 1 year, said Lorretta Nastoupil, MD, of MD Anderson Cancer Center in Houston, Texas.

 

She presented results with the treatment at the 14th International Conference on Malignant Lymphoma (ICML).

 

The research was sponsored by TG Therapeutics, the company developing ublituximab (TG-1101) and umbralisib (TGR-1202).

 

Patients and treatment

 

Dr Nastoupil presented data on 38 patients—20 with CLL/SLL, and 18 with NHL. Three of the CLL/SLL patients were treatment-naïve. The rest had relapsed/refractory disease.

 

All NHL patients had relapsed/refractory disease—6 with DLBCL, 6 with FL, 4 with MCL, and 2 with MZL.

 

For the entire cohort, the median age was 65 (range, 32-85), and most patients (n=29) were male. They had received a median of 3 prior treatment regimens (range, 0-6).

 

In this trial, the patients received:

 

 

 

 

 

• Ublituximab at 900 mg
• Ibrutinib at 420 mg (CLL/SLL) or 560 mg (NHL)
• Umbralisib at 400 mg, 600 mg, or 800 mg.

Eighty-one percent of patients have been on study for more than 6 months. The median time on study is 11.1 months (range, 0.4 to 30+ months).

 

Safety

 

There was 1 dose-limiting toxicity in the CLL cohort (umbralisib at 400 mg)—reactivated varicella zoster. And 2 patients discontinued treatment due to an adverse event (AE)—1 due to sepsis and 1 due to pneumonia.

 

Neutropenia (18%) and pneumonia (11%) were the only grade 3/4 AEs that occurred in more than 10% of patients. Other grade 3/4 AEs included thrombocytopenia (8%), diarrhea (3%), dizziness (3%), pyrexia (3%), rash (3%), anemia (3%), dyspnea (3%), and stomatitis (3%).

 

The most common AEs of any grade were diarrhea (47%), fatigue (47%), dizziness (37%), insomnia (34%), nausea (34%), neutropenia (32%), cough (32%), and infusion-related reactions (32%).

 

Efficacy

 

Thirty-six patients were evaluable for efficacy—19 with CLL/SLL and 17 with NHL patients. Two patients discontinued treatment before the first efficacy assessment—1 due to pneumonia and 1 at investigator discretion.

 

For the entire cohort, the overall response rate (ORR) was 83%.

 

In the CLL/SLL cohort, the ORR was 100% (19/19), and the complete response (CR) rate was 32% (n=6). However, 4 of the 6 CRs are pending bone marrow confirmation.

 

Dr Nastoupil noted that 8 of the CLL patients had a 17p and/or 11q deletion, and 3 had previously received treatment with a BTK and/or PI3Kδ inhibitor.

 

One patient who was refractory to both idelalisib and ibrutinib achieved a CR with the triplet regimen, and this response has been ongoing for more than 1.5 years.

 

Among patients with NHL, the ORR was 100% in patients with MZL (2/2) and MCL (4/4). The ORR was 80% (4/5) in FL patients, and 17% (1/6) in DLBCL patients.

 

The CR rate was 50% in patients with MZL (1/2) and MCL (2/4) and 20% in patients with FL (1/5).

 

Dr Nastoupil pointed out that the FL patients were heavily pretreated. Two of them had received an autologous stem cell transplant, 1 was refractory to prior ibrutinib treatment, and 1 had received 5 prior lines of rituximab-based therapy.

 

She also noted that the DLBCL patients had a median of 4 prior therapies, and 4 of these patients had non-GCB DLBCL, including the only patient who responded to the triplet.

 

 

“[T]he combination of ublituximab, umbralisib, and ibrutinib in advanced CLL and NHL demonstrated a favorable toxicity profile as well as favorable efficacy,” Dr Nastoupil said in closing.

 

“[This] suggests umbralisib may be safely combined with other targeted agents to overcome mechanisms of resistance.” 

 

Mantle cell lymphoma

 

LUGANO, SWITZERLAND—A chemotherapy-free combination regimen has demonstrated “favorable” safety and efficacy in patients with advanced chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and non-Hodgkin lymphoma (NHL), according to researchers.

 

They found that treatment with ublituximab, umbralisib, and ibrutinib produced responses in patients with CLL/SLL, marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL).

 

Many of these patients are still receiving the combination, some of them beyond 1 year, said Lorretta Nastoupil, MD, of MD Anderson Cancer Center in Houston, Texas.

 

She presented results with the treatment at the 14th International Conference on Malignant Lymphoma (ICML).

 

The research was sponsored by TG Therapeutics, the company developing ublituximab (TG-1101) and umbralisib (TGR-1202).

 

Patients and treatment

 

Dr Nastoupil presented data on 38 patients—20 with CLL/SLL, and 18 with NHL. Three of the CLL/SLL patients were treatment-naïve. The rest had relapsed/refractory disease.

 

All NHL patients had relapsed/refractory disease—6 with DLBCL, 6 with FL, 4 with MCL, and 2 with MZL.

 

For the entire cohort, the median age was 65 (range, 32-85), and most patients (n=29) were male. They had received a median of 3 prior treatment regimens (range, 0-6).

 

In this trial, the patients received:

 

 

 

 

 

• Ublituximab at 900 mg
• Ibrutinib at 420 mg (CLL/SLL) or 560 mg (NHL)
• Umbralisib at 400 mg, 600 mg, or 800 mg.

Eighty-one percent of patients have been on study for more than 6 months. The median time on study is 11.1 months (range, 0.4 to 30+ months).

 

Safety

 

There was 1 dose-limiting toxicity in the CLL cohort (umbralisib at 400 mg)—reactivated varicella zoster. And 2 patients discontinued treatment due to an adverse event (AE)—1 due to sepsis and 1 due to pneumonia.

 

Neutropenia (18%) and pneumonia (11%) were the only grade 3/4 AEs that occurred in more than 10% of patients. Other grade 3/4 AEs included thrombocytopenia (8%), diarrhea (3%), dizziness (3%), pyrexia (3%), rash (3%), anemia (3%), dyspnea (3%), and stomatitis (3%).

 

The most common AEs of any grade were diarrhea (47%), fatigue (47%), dizziness (37%), insomnia (34%), nausea (34%), neutropenia (32%), cough (32%), and infusion-related reactions (32%).

 

Efficacy

 

Thirty-six patients were evaluable for efficacy—19 with CLL/SLL and 17 with NHL patients. Two patients discontinued treatment before the first efficacy assessment—1 due to pneumonia and 1 at investigator discretion.

 

For the entire cohort, the overall response rate (ORR) was 83%.

 

In the CLL/SLL cohort, the ORR was 100% (19/19), and the complete response (CR) rate was 32% (n=6). However, 4 of the 6 CRs are pending bone marrow confirmation.

 

Dr Nastoupil noted that 8 of the CLL patients had a 17p and/or 11q deletion, and 3 had previously received treatment with a BTK and/or PI3Kδ inhibitor.

 

One patient who was refractory to both idelalisib and ibrutinib achieved a CR with the triplet regimen, and this response has been ongoing for more than 1.5 years.

 

Among patients with NHL, the ORR was 100% in patients with MZL (2/2) and MCL (4/4). The ORR was 80% (4/5) in FL patients, and 17% (1/6) in DLBCL patients.

 

The CR rate was 50% in patients with MZL (1/2) and MCL (2/4) and 20% in patients with FL (1/5).

 

Dr Nastoupil pointed out that the FL patients were heavily pretreated. Two of them had received an autologous stem cell transplant, 1 was refractory to prior ibrutinib treatment, and 1 had received 5 prior lines of rituximab-based therapy.

 

She also noted that the DLBCL patients had a median of 4 prior therapies, and 4 of these patients had non-GCB DLBCL, including the only patient who responded to the triplet.

 

 

“[T]he combination of ublituximab, umbralisib, and ibrutinib in advanced CLL and NHL demonstrated a favorable toxicity profile as well as favorable efficacy,” Dr Nastoupil said in closing.

 

“[This] suggests umbralisib may be safely combined with other targeted agents to overcome mechanisms of resistance.” 

 

The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).

The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.

The combination is not indicated for the treatment of nonmalignant conditions.

Approval was based on noninferior rituximab trough concentrations for the subcutaneously administered combination, compared with intravenous rituximab, and comparable efficacy and safety results as shown in multiple randomized clinical trials.

The most common adverse events seen with the combination in patients with FL included infections, neutropenia, nausea, constipation, cough, and fatigue. In patients with DLBCL, the most common adverse events were infections, neutropenia, alopecia, nausea, and anemia; in CLL patients, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema occurred most commonly.

The combination is indicated for the following previously approved indications for rituximab:

• Relapsed or refractory FL as a single agent.
• Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
• Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
• Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
• Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.

The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.

Rituxan Hycela is marketed by Genentech.

[email protected]

 

The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).

The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.

The combination is not indicated for the treatment of nonmalignant conditions.

Approval was based on noninferior rituximab trough concentrations for the subcutaneously administered combination, compared with intravenous rituximab, and comparable efficacy and safety results as shown in multiple randomized clinical trials.

The most common adverse events seen with the combination in patients with FL included infections, neutropenia, nausea, constipation, cough, and fatigue. In patients with DLBCL, the most common adverse events were infections, neutropenia, alopecia, nausea, and anemia; in CLL patients, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema occurred most commonly.

The combination is indicated for the following previously approved indications for rituximab:

• Relapsed or refractory FL as a single agent.
• Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
• Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
• Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
• Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.

The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.

Rituxan Hycela is marketed by Genentech.

[email protected]

 

The Food and Drug Administration has approved rituximab plus hyaluronidase human for adult patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).

The combination product, to be marketed as Rituxan Hycela, is administered subcutaneously, shortening administration time to 5 to 7 minutes as compared with the several hours needed for intravenous infusion, the FDA said in a statement.

The combination is not indicated for the treatment of nonmalignant conditions.

Approval was based on noninferior rituximab trough concentrations for the subcutaneously administered combination, compared with intravenous rituximab, and comparable efficacy and safety results as shown in multiple randomized clinical trials.

The most common adverse events seen with the combination in patients with FL included infections, neutropenia, nausea, constipation, cough, and fatigue. In patients with DLBCL, the most common adverse events were infections, neutropenia, alopecia, nausea, and anemia; in CLL patients, infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema occurred most commonly.

The combination is indicated for the following previously approved indications for rituximab:

• Relapsed or refractory FL as a single agent.
• Previously untreated FL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.
• Nonprogressing (including stable disease) FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone chemotherapy.
• Previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone or other anthracycline-based chemotherapy regimens.
• Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide.

The recommended doses are 1,400 mg rituximab and 23,400 units hyaluronidase human for FL and DLBCL and 1,600 mg rituximab and 26,800 units hyaluronidase human for CLL. The combination treatment should be initiated only after patients have received at least one full dose of a rituximab product by intravenous infusion, according to the prescribing information.

Rituxan Hycela is marketed by Genentech.

[email protected]

 

14th International Conference on Malignant Lymphoma (ICML)

 

LUGANO, SWITZERLAND—Interim results of a phase 2 trial suggest tazemetostat can be effective in patients with heavily pretreated, relapsed or refractory non-Hodgkin lymphoma.

 

The EZH2 inhibitor produced the highest overall response rate in patients with EZH2-mutated follicular lymphoma (FL), followed by EZH2-mutated diffuse large B-cell lymphoma (DLBCL).

 

However, the drug also produced complete responses in FL and DLBCL patients with wild-type EZH2.

 

“If we had focused [only] on patients with EZH2 mutations, we would have missed those other complete responders in the wild-type setting,” said study investigator Franck Morschhauser, MD, PhD, of Centre Hospitalier Régional Universitaire de Lille in France.

 

He presented results of the trial* during the plenary session of the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by Epizyme, the company developing tazemetostat.

 

The trial enrolled patients with relapsed or refractory DLBCL or FL who had received at least 2 prior therapies. The patients received tazemetostat at 800 mg twice daily until disease progression or study withdrawal.

 

Efficacy in FL

 

Dr Morschhauser presented efficacy data on 67 patients with FL. Thirteen had EZH2 mutations, and 54 had wild-type EZH2. The median age was 62 in the mutated group and 61 in the wild-type group.

 

Both groups had a median of 4 prior lines of therapy. Fifty-four percent of EZH2-mutated patients were refractory to their last treatment, as were 48% of wild-type patients.

 

The median time from diagnosis was 7.4 years in mutated patients and 4.9 years in wild-type patients. The median time from last therapy was 13 weeks and 41.3 weeks, respectively.

 

The overall response rate was 92% (12/13) in EZH2-mutated patients and 26% (14/54) in wild-type patients. The complete response rates were 8% (n=1) and 6% (n=3), respectively.

 

The median time to first response was 11.9 weeks and 15.2 weeks, respectively.

 

None of the EZH2-mutated patients have progressed, but 13 (24%) wild-type patients have.

 

Forty-eight percent of all FL patients remain on study. One EZH2-mutated patient with stable disease is still on study, as are 23 wild-type patients with stable disease.

 

Efficacy in DLBCL

 

Dr Morschhauser presented data on 137 patients with DLBCL, 17 with EZH2 mutations and 120 with wild-type EZH2. The median age was 61 in the mutated group and 69 in the wild-type group.

 

Both groups had a median of 3 prior lines of therapy. Eighty-two percent of EZH2-mutated patients were refractory to their last treatment, as were 63% of wild-type patients.

 

The median time from diagnosis was 1 year in mutated patients and 2 years in wild-type patients. The median time from last therapy was 8.6 weeks and 11.6 weeks, respectively.

 

The overall response rate was 29% (5/17) in EZH2-mutated patients and 15% (18/119) in wild-type patients. The complete response rates were 0% (n=0) and 8% (n=10), respectively.

 

The median time to first response was 8.3 weeks and 8.5 weeks, respectively.

 

Six (35%) of the EZH2-mutated patients have progressed, as have 60 (50%) wild-type patients.

 

Twelve percent of all DLBCL patients remain on study. One EZH2-mutated patient with stable disease is still on therapy, as are 4 wild-type patients with stable disease.

 

Predictors of response

 

Dr Morschhauser and his colleagues performed next-generation sequencing of samples from 92 patients in an attempt to identify predictors of response to tazemetostat.

 

The data suggested that EZH2 and MYD88 activating mutations are positive predictors of response, and negative predictors include MYC, TP53, and HIST1H1E.

 

Safety

 

Safety data were available for 210 patients. The overall rate of treatment-related adverse events (AEs) was 59%, the rate of grade 3 or higher treatment-related AEs was 18%, and the rate of serious treatment-related AEs was 10%.

 

 

There were treatment-related AEs leading to dose interruption (15%), dose reduction (3%), and discontinuation of tazemetostat (2%).

 

The most common treatment-related AEs were nausea (14%), thrombocytopenia (13%), anemia (10%), neutropenia (9%), diarrhea (8%), asthenia (8%), and fatigue (7%).

 

Dr Morschhauser said these results “confirm that tazemetostat is quite safe” in this patient population, and enrollment in this trial is ongoing. 

 

*Data in the abstract differ from the presentation.

 

14th International Conference on Malignant Lymphoma (ICML)

 

LUGANO, SWITZERLAND—Interim results of a phase 2 trial suggest tazemetostat can be effective in patients with heavily pretreated, relapsed or refractory non-Hodgkin lymphoma.

 

The EZH2 inhibitor produced the highest overall response rate in patients with EZH2-mutated follicular lymphoma (FL), followed by EZH2-mutated diffuse large B-cell lymphoma (DLBCL).

 

However, the drug also produced complete responses in FL and DLBCL patients with wild-type EZH2.

 

“If we had focused [only] on patients with EZH2 mutations, we would have missed those other complete responders in the wild-type setting,” said study investigator Franck Morschhauser, MD, PhD, of Centre Hospitalier Régional Universitaire de Lille in France.

 

He presented results of the trial* during the plenary session of the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by Epizyme, the company developing tazemetostat.

 

The trial enrolled patients with relapsed or refractory DLBCL or FL who had received at least 2 prior therapies. The patients received tazemetostat at 800 mg twice daily until disease progression or study withdrawal.

 

Efficacy in FL

 

Dr Morschhauser presented efficacy data on 67 patients with FL. Thirteen had EZH2 mutations, and 54 had wild-type EZH2. The median age was 62 in the mutated group and 61 in the wild-type group.

 

Both groups had a median of 4 prior lines of therapy. Fifty-four percent of EZH2-mutated patients were refractory to their last treatment, as were 48% of wild-type patients.

 

The median time from diagnosis was 7.4 years in mutated patients and 4.9 years in wild-type patients. The median time from last therapy was 13 weeks and 41.3 weeks, respectively.

 

The overall response rate was 92% (12/13) in EZH2-mutated patients and 26% (14/54) in wild-type patients. The complete response rates were 8% (n=1) and 6% (n=3), respectively.

 

The median time to first response was 11.9 weeks and 15.2 weeks, respectively.

 

None of the EZH2-mutated patients have progressed, but 13 (24%) wild-type patients have.

 

Forty-eight percent of all FL patients remain on study. One EZH2-mutated patient with stable disease is still on study, as are 23 wild-type patients with stable disease.

 

Efficacy in DLBCL

 

Dr Morschhauser presented data on 137 patients with DLBCL, 17 with EZH2 mutations and 120 with wild-type EZH2. The median age was 61 in the mutated group and 69 in the wild-type group.

 

Both groups had a median of 3 prior lines of therapy. Eighty-two percent of EZH2-mutated patients were refractory to their last treatment, as were 63% of wild-type patients.

 

The median time from diagnosis was 1 year in mutated patients and 2 years in wild-type patients. The median time from last therapy was 8.6 weeks and 11.6 weeks, respectively.

 

The overall response rate was 29% (5/17) in EZH2-mutated patients and 15% (18/119) in wild-type patients. The complete response rates were 0% (n=0) and 8% (n=10), respectively.

 

The median time to first response was 8.3 weeks and 8.5 weeks, respectively.

 

Six (35%) of the EZH2-mutated patients have progressed, as have 60 (50%) wild-type patients.

 

Twelve percent of all DLBCL patients remain on study. One EZH2-mutated patient with stable disease is still on therapy, as are 4 wild-type patients with stable disease.

 

Predictors of response

 

Dr Morschhauser and his colleagues performed next-generation sequencing of samples from 92 patients in an attempt to identify predictors of response to tazemetostat.

 

The data suggested that EZH2 and MYD88 activating mutations are positive predictors of response, and negative predictors include MYC, TP53, and HIST1H1E.

 

Safety

 

Safety data were available for 210 patients. The overall rate of treatment-related adverse events (AEs) was 59%, the rate of grade 3 or higher treatment-related AEs was 18%, and the rate of serious treatment-related AEs was 10%.

 

 

There were treatment-related AEs leading to dose interruption (15%), dose reduction (3%), and discontinuation of tazemetostat (2%).

 

The most common treatment-related AEs were nausea (14%), thrombocytopenia (13%), anemia (10%), neutropenia (9%), diarrhea (8%), asthenia (8%), and fatigue (7%).

 

Dr Morschhauser said these results “confirm that tazemetostat is quite safe” in this patient population, and enrollment in this trial is ongoing. 

 

*Data in the abstract differ from the presentation.

 

14th International Conference on Malignant Lymphoma (ICML)

 

LUGANO, SWITZERLAND—Interim results of a phase 2 trial suggest tazemetostat can be effective in patients with heavily pretreated, relapsed or refractory non-Hodgkin lymphoma.

 

The EZH2 inhibitor produced the highest overall response rate in patients with EZH2-mutated follicular lymphoma (FL), followed by EZH2-mutated diffuse large B-cell lymphoma (DLBCL).

 

However, the drug also produced complete responses in FL and DLBCL patients with wild-type EZH2.

 

“If we had focused [only] on patients with EZH2 mutations, we would have missed those other complete responders in the wild-type setting,” said study investigator Franck Morschhauser, MD, PhD, of Centre Hospitalier Régional Universitaire de Lille in France.

 

He presented results of the trial* during the plenary session of the 14th International Conference on Malignant Lymphoma (ICML). The research was sponsored by Epizyme, the company developing tazemetostat.

 

The trial enrolled patients with relapsed or refractory DLBCL or FL who had received at least 2 prior therapies. The patients received tazemetostat at 800 mg twice daily until disease progression or study withdrawal.

 

Efficacy in FL

 

Dr Morschhauser presented efficacy data on 67 patients with FL. Thirteen had EZH2 mutations, and 54 had wild-type EZH2. The median age was 62 in the mutated group and 61 in the wild-type group.

 

Both groups had a median of 4 prior lines of therapy. Fifty-four percent of EZH2-mutated patients were refractory to their last treatment, as were 48% of wild-type patients.

 

The median time from diagnosis was 7.4 years in mutated patients and 4.9 years in wild-type patients. The median time from last therapy was 13 weeks and 41.3 weeks, respectively.

 

The overall response rate was 92% (12/13) in EZH2-mutated patients and 26% (14/54) in wild-type patients. The complete response rates were 8% (n=1) and 6% (n=3), respectively.

 

The median time to first response was 11.9 weeks and 15.2 weeks, respectively.

 

None of the EZH2-mutated patients have progressed, but 13 (24%) wild-type patients have.

 

Forty-eight percent of all FL patients remain on study. One EZH2-mutated patient with stable disease is still on study, as are 23 wild-type patients with stable disease.

 

Efficacy in DLBCL

 

Dr Morschhauser presented data on 137 patients with DLBCL, 17 with EZH2 mutations and 120 with wild-type EZH2. The median age was 61 in the mutated group and 69 in the wild-type group.

 

Both groups had a median of 3 prior lines of therapy. Eighty-two percent of EZH2-mutated patients were refractory to their last treatment, as were 63% of wild-type patients.

 

The median time from diagnosis was 1 year in mutated patients and 2 years in wild-type patients. The median time from last therapy was 8.6 weeks and 11.6 weeks, respectively.

 

The overall response rate was 29% (5/17) in EZH2-mutated patients and 15% (18/119) in wild-type patients. The complete response rates were 0% (n=0) and 8% (n=10), respectively.

 

The median time to first response was 8.3 weeks and 8.5 weeks, respectively.

 

Six (35%) of the EZH2-mutated patients have progressed, as have 60 (50%) wild-type patients.

 

Twelve percent of all DLBCL patients remain on study. One EZH2-mutated patient with stable disease is still on therapy, as are 4 wild-type patients with stable disease.

 

Predictors of response

 

Dr Morschhauser and his colleagues performed next-generation sequencing of samples from 92 patients in an attempt to identify predictors of response to tazemetostat.

 

The data suggested that EZH2 and MYD88 activating mutations are positive predictors of response, and negative predictors include MYC, TP53, and HIST1H1E.

 

Safety

 

Safety data were available for 210 patients. The overall rate of treatment-related adverse events (AEs) was 59%, the rate of grade 3 or higher treatment-related AEs was 18%, and the rate of serious treatment-related AEs was 10%.

 

 

There were treatment-related AEs leading to dose interruption (15%), dose reduction (3%), and discontinuation of tazemetostat (2%).

 

The most common treatment-related AEs were nausea (14%), thrombocytopenia (13%), anemia (10%), neutropenia (9%), diarrhea (8%), asthenia (8%), and fatigue (7%).

 

Dr Morschhauser said these results “confirm that tazemetostat is quite safe” in this patient population, and enrollment in this trial is ongoing. 

 

*Data in the abstract differ from the presentation.