Lymphoma & Plasma Cell Disorders

An early study adding palbociclib to ibrutinib in previously treated patients with mantle cell lymphoma (MCL) showed a higher complete response rate than what has previously been reported for single-agent ibrutinib, according to investigators.

Results from the phase 1 trial (NCT02159755) support preclinical models, suggesting that the CDK4/6 inhibitor palbociclib may be able to help overcome resistance to ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK).

These findings set the stage for an ongoing phase 2 multicenter study, reported lead author Peter Martin, MD, of Weill Cornell Medicine in New York and his colleagues.

The present study involved 27 patients with previously treated MCL, the investigators wrote in Blood. Of these, 21 were men and 6 were women, all of whom had adequate organ and bone marrow function, good performance status, and no previous treatment with CDK4/6 or BTK inhibitors.

Patients were randomly grouped into five dose levels of each drug: Ibrutinib doses ranged from 280-560 mg, and palbociclib from 75-125 mg. Ibrutinib was given daily and palbociclib was administered for 21 out of 28 days per cycle. Therapy continued until withdrawal, unacceptable toxicity, or disease progression.

The primary objective was to determine phase 2 dose. Secondarily, the investigators sought to determine activity and toxicity profiles. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1-21 of each 28-day cycle.

Across all patients, the complete response rate was 37%, compared with 21% for ibrutinib monotherapy in a previous trial. About two-thirds of patients had a response of any kind, which aligns closely with the overall response rate previously reported for ibrutinib alone (67% vs. 68%). After a median follow-up of 25.6 months in survivors, the 2-year progression free survival was 59.4%. The two-year overall survival rate was 60.6%.

The dose-limiting toxicity was grade 3 rash, which occurred in two out of five patients treated at the highest doses. The most common grade 3 or higher toxicities were neutropenia (41%) and thrombocytopenia (30%), followed by hypertension (15%), febrile neutropenia (15%), lung infection (11%), fatigue (7%), upper respiratory tract infection (7%), hyperglycemia (7%), rash (7%), myalgia (7%), and increased alanine transaminase/aspartate aminotransferase (7%).

“Although BTK-inhibitor-based combinations appear promising, the degree to which they improve upon single-agent ibrutinib is unclear,” the investigators wrote, noting that a phase 2 trial (NCT03478514) is currently underway and uses the maximum tolerated doses.

The phase 1 trial was sponsored by the National Cancer Institute. Study funding was provided by the Sarah Cannon Fund at the HCA Foundation. The investigators reported financial relationships with Janssen, Gilead, AstraZeneca, Celgene, Karyopharm, and others.

SOURCE: Martin P et al. Blood. 2019 Jan 28. doi: 10.1182/blood-2018-11-886457.

An early study adding palbociclib to ibrutinib in previously treated patients with mantle cell lymphoma (MCL) showed a higher complete response rate than what has previously been reported for single-agent ibrutinib, according to investigators.

Results from the phase 1 trial (NCT02159755) support preclinical models, suggesting that the CDK4/6 inhibitor palbociclib may be able to help overcome resistance to ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK).

These findings set the stage for an ongoing phase 2 multicenter study, reported lead author Peter Martin, MD, of Weill Cornell Medicine in New York and his colleagues.

The present study involved 27 patients with previously treated MCL, the investigators wrote in Blood. Of these, 21 were men and 6 were women, all of whom had adequate organ and bone marrow function, good performance status, and no previous treatment with CDK4/6 or BTK inhibitors.

Patients were randomly grouped into five dose levels of each drug: Ibrutinib doses ranged from 280-560 mg, and palbociclib from 75-125 mg. Ibrutinib was given daily and palbociclib was administered for 21 out of 28 days per cycle. Therapy continued until withdrawal, unacceptable toxicity, or disease progression.

The primary objective was to determine phase 2 dose. Secondarily, the investigators sought to determine activity and toxicity profiles. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1-21 of each 28-day cycle.

Across all patients, the complete response rate was 37%, compared with 21% for ibrutinib monotherapy in a previous trial. About two-thirds of patients had a response of any kind, which aligns closely with the overall response rate previously reported for ibrutinib alone (67% vs. 68%). After a median follow-up of 25.6 months in survivors, the 2-year progression free survival was 59.4%. The two-year overall survival rate was 60.6%.

The dose-limiting toxicity was grade 3 rash, which occurred in two out of five patients treated at the highest doses. The most common grade 3 or higher toxicities were neutropenia (41%) and thrombocytopenia (30%), followed by hypertension (15%), febrile neutropenia (15%), lung infection (11%), fatigue (7%), upper respiratory tract infection (7%), hyperglycemia (7%), rash (7%), myalgia (7%), and increased alanine transaminase/aspartate aminotransferase (7%).

“Although BTK-inhibitor-based combinations appear promising, the degree to which they improve upon single-agent ibrutinib is unclear,” the investigators wrote, noting that a phase 2 trial (NCT03478514) is currently underway and uses the maximum tolerated doses.

The phase 1 trial was sponsored by the National Cancer Institute. Study funding was provided by the Sarah Cannon Fund at the HCA Foundation. The investigators reported financial relationships with Janssen, Gilead, AstraZeneca, Celgene, Karyopharm, and others.

SOURCE: Martin P et al. Blood. 2019 Jan 28. doi: 10.1182/blood-2018-11-886457.

An early study adding palbociclib to ibrutinib in previously treated patients with mantle cell lymphoma (MCL) showed a higher complete response rate than what has previously been reported for single-agent ibrutinib, according to investigators.

Results from the phase 1 trial (NCT02159755) support preclinical models, suggesting that the CDK4/6 inhibitor palbociclib may be able to help overcome resistance to ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK).

These findings set the stage for an ongoing phase 2 multicenter study, reported lead author Peter Martin, MD, of Weill Cornell Medicine in New York and his colleagues.

The present study involved 27 patients with previously treated MCL, the investigators wrote in Blood. Of these, 21 were men and 6 were women, all of whom had adequate organ and bone marrow function, good performance status, and no previous treatment with CDK4/6 or BTK inhibitors.

Patients were randomly grouped into five dose levels of each drug: Ibrutinib doses ranged from 280-560 mg, and palbociclib from 75-125 mg. Ibrutinib was given daily and palbociclib was administered for 21 out of 28 days per cycle. Therapy continued until withdrawal, unacceptable toxicity, or disease progression.

The primary objective was to determine phase 2 dose. Secondarily, the investigators sought to determine activity and toxicity profiles. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1-21 of each 28-day cycle.

Across all patients, the complete response rate was 37%, compared with 21% for ibrutinib monotherapy in a previous trial. About two-thirds of patients had a response of any kind, which aligns closely with the overall response rate previously reported for ibrutinib alone (67% vs. 68%). After a median follow-up of 25.6 months in survivors, the 2-year progression free survival was 59.4%. The two-year overall survival rate was 60.6%.

The dose-limiting toxicity was grade 3 rash, which occurred in two out of five patients treated at the highest doses. The most common grade 3 or higher toxicities were neutropenia (41%) and thrombocytopenia (30%), followed by hypertension (15%), febrile neutropenia (15%), lung infection (11%), fatigue (7%), upper respiratory tract infection (7%), hyperglycemia (7%), rash (7%), myalgia (7%), and increased alanine transaminase/aspartate aminotransferase (7%).

“Although BTK-inhibitor-based combinations appear promising, the degree to which they improve upon single-agent ibrutinib is unclear,” the investigators wrote, noting that a phase 2 trial (NCT03478514) is currently underway and uses the maximum tolerated doses.

The phase 1 trial was sponsored by the National Cancer Institute. Study funding was provided by the Sarah Cannon Fund at the HCA Foundation. The investigators reported financial relationships with Janssen, Gilead, AstraZeneca, Celgene, Karyopharm, and others.

SOURCE: Martin P et al. Blood. 2019 Jan 28. doi: 10.1182/blood-2018-11-886457.

The European Commission (EC) has approved brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).

This is the fifth approved indication for BV (Adcetris) in Europe. The drug is already EC approved to treat adults with CD30+ HL at increased risk of relapse or progression after autologous stem cell transplant (ASCT); relapsed or refractory, CD30+ HL after ASCT or at least two prior therapies when ASCT or multi-agent chemotherapy is not an option; relapsed or refractory systemic anaplastic large-cell lymphoma; and CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.

The EC’s approval of BV plus AVD is supported by the phase 3 ECHELON-1 trial (N Engl J Med. 2018;378:331-44).

ECHELON-1 included 1,334 patients with advanced HL who received BV plus AVD (n = 664) or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD, n = 670) as frontline treatment.

The study's primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, BV plus AVD provided a significant improvement in modified PFS. The 2-year modified PFS rate was 82% in the BV-AVD arm and 77% in the ABVD arm (hazard ratio = 0.77; P = .04).

There was no significant difference between the treatment arms in response rates or overall survival.

The overall incidence of adverse events (AEs) was 99% in the BV-AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively. The incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV-AVD, while pulmonary toxicity was more common with ABVD.

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals (a Takeda company) in collaboration with Seattle Genetics.

[email protected]

The European Commission (EC) has approved brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).

This is the fifth approved indication for BV (Adcetris) in Europe. The drug is already EC approved to treat adults with CD30+ HL at increased risk of relapse or progression after autologous stem cell transplant (ASCT); relapsed or refractory, CD30+ HL after ASCT or at least two prior therapies when ASCT or multi-agent chemotherapy is not an option; relapsed or refractory systemic anaplastic large-cell lymphoma; and CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.

The EC’s approval of BV plus AVD is supported by the phase 3 ECHELON-1 trial (N Engl J Med. 2018;378:331-44).

ECHELON-1 included 1,334 patients with advanced HL who received BV plus AVD (n = 664) or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD, n = 670) as frontline treatment.

The study's primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, BV plus AVD provided a significant improvement in modified PFS. The 2-year modified PFS rate was 82% in the BV-AVD arm and 77% in the ABVD arm (hazard ratio = 0.77; P = .04).

There was no significant difference between the treatment arms in response rates or overall survival.

The overall incidence of adverse events (AEs) was 99% in the BV-AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively. The incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV-AVD, while pulmonary toxicity was more common with ABVD.

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals (a Takeda company) in collaboration with Seattle Genetics.

[email protected]

The European Commission (EC) has approved brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) to treat adults with previously untreated, CD30+, stage IV Hodgkin lymphoma (HL).

This is the fifth approved indication for BV (Adcetris) in Europe. The drug is already EC approved to treat adults with CD30+ HL at increased risk of relapse or progression after autologous stem cell transplant (ASCT); relapsed or refractory, CD30+ HL after ASCT or at least two prior therapies when ASCT or multi-agent chemotherapy is not an option; relapsed or refractory systemic anaplastic large-cell lymphoma; and CD30+ cutaneous T-cell lymphoma after at least one prior systemic therapy.

The EC’s approval of BV plus AVD is supported by the phase 3 ECHELON-1 trial (N Engl J Med. 2018;378:331-44).

ECHELON-1 included 1,334 patients with advanced HL who received BV plus AVD (n = 664) or doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD, n = 670) as frontline treatment.

The study's primary endpoint was modified progression-free survival (PFS), which was defined as time to progression, death, or evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy.

According to an independent review committee, BV plus AVD provided a significant improvement in modified PFS. The 2-year modified PFS rate was 82% in the BV-AVD arm and 77% in the ABVD arm (hazard ratio = 0.77; P = .04).

There was no significant difference between the treatment arms in response rates or overall survival.

The overall incidence of adverse events (AEs) was 99% in the BV-AVD arm and 98% in the ABVD arm. The incidence of grade 3 or higher AEs was 83% and 66%, respectively. The incidence of serious AEs was 43% and 27%, respectively.

Neutropenia, febrile neutropenia, and peripheral neuropathy were more common with BV-AVD, while pulmonary toxicity was more common with ABVD.

The ECHELON-1 trial was sponsored by Millennium Pharmaceuticals (a Takeda company) in collaboration with Seattle Genetics.

[email protected]

Nivolumab may provide a benefit for a small group of patients with diffuse large B-cell lymphoma (DLBCL) who have failed a transplant or are ineligible for one, according to researchers.

Nivolumab produced a response in 10 of 121 DLBCL patients studied. Three patients achieved a complete response (CR) lasting 11 months or more.

Why this small group responded to nivolumab isn’t clear, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minn., and his colleagues.

Some responders did have 9p24.1 alterations, but others did not. None of the responders had tumor cells positive for programmed death–ligand 1 (PD-L1), and only one responder had detectable PD-L2 expression in malignant cells.

Dr. Ansell and his colleagues described these findings in the Journal of Clinical Oncology.

The researchers evaluated nivolumab in a phase 2 trial (NCT02038933) of patients with relapsed/refractory DLBCL. Of the 121 patients, 87 had failed autologous hematopoietic stem cell transplant (HSCT) and 34 were ineligible for autologous HSCT. The patients received nivolumab at 3 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or study withdrawal.

HSCT failures

The patients who had failed HSCT had a median age of 62 years (range, 24-75 years). They had received a median of three prior systemic therapies (range, 1-11), and 28% were refractory to their most recent therapy.

About 40% of patients had germinal center B-cell–like (GCB) DLBCL, 32% had non-GCB disease, and data on disease subtype were missing for the rest of the group.

The patients received a median of four nivolumab doses (range, 1-44) and were followed for a median of 9 months (range, 0.1-25 months).

Nine patients (10%) achieved a response, and the median duration of response was 11 months. Responses occurred in patients with GCB and non-GCB DLBCL.

Three patients achieved a CR. Two of them were still on treatment and in CR at the data cutoff. Their responses had lasted 11 months and 14 months, respectively. The third complete responder did not progress on nivolumab but developed myelodysplastic syndrome, which was unrelated to the drug, and died.

Among all patients who had failed HSCT, the median progression-free survival was 1.9 months, and the median overall survival was 12.2 months.

Seven patients in this group were still receiving nivolumab at the data cutoff. Two of them were in CR, two had a partial response, and three had stable disease.

HSCT-ineligible group

The patients who were ineligible for HSCT had a median age of 68 years (range, 28-86 years). They had received a median of three prior systemic therapies (range, 1-7), and 59% were refractory to their most recent therapy.

About 56% of these patients had GCB DLBCL, 18% had non-GCB disease, and data on subtype were missing for the rest of the group.

The patients received a median of three nivolumab doses (range, 1-22) and were followed for a median of 6 months (range, 0.2-24 months). One patient (3%) achieved a partial response, which lasted 8.3 months.

The median progression-free survival in this group was 1.4 months, and the median overall survival was 5.8 months.

None of the patients in this group were still taking nivolumab at the data cutoff.

Biomarkers of response

Dr. Ansell and his colleagues were able to look for 9p24.1 alterations in archival tumor biopsy specimens from 74 patients. The team reported that 9p24.1 alterations were “infrequent,” but they were found in some responders.

Among the three complete responders, one patient had high-level 9p24.1 amplification, one had normal 9p24.1 copy number, and one did not have a biopsy available.

Among the seven patients who achieved a partial response, five had biopsy specimens. Three patients had low-level polysomy, one had copy gain, and one patient had normal 9p24.1.

None of the responders had PD-L1 expression in their tumor cells, but one complete responder had PD-L2–positive malignant cells.

Dr. Ansell and his colleagues wrote that the “biologic basis for response in the other two [complete responders] is unclear,” and the researchers were unable to assess associations between response and c-myc expression or double-hit lymphoma.

Safety

Of all 121 patients, 62% had a treatment-related adverse event (AE) and 24% had a grade 3/4–related AE.

The most common related AEs of any grade were nausea (17%), fatigue (17%), diarrhea (10%), neutropenia (7%), thrombocytopenia (6%), decreased appetite (6%), lipase increase (5%), rash (5%), and pyrexia (5%).

Four patients (3%) stopped taking nivolumab because of treatment-related AEs, including neutropenia, thrombocytopenia, diarrhea, pancreatitis, lipase increase, and psoriasiform dermatitis. There were no fatal treatment-related AEs.

This research was supported by Bristol-Myers Squibb and other groups. The study authors reported relationships with Bristol-Myers Squibb and other companies.

[email protected]

SOURCE: Ansell SM et al. J Clin Oncol. 2019 Jan 8. doi: 10.1200/JCO.18.00766.

Nivolumab may provide a benefit for a small group of patients with diffuse large B-cell lymphoma (DLBCL) who have failed a transplant or are ineligible for one, according to researchers.

Nivolumab produced a response in 10 of 121 DLBCL patients studied. Three patients achieved a complete response (CR) lasting 11 months or more.

Why this small group responded to nivolumab isn’t clear, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minn., and his colleagues.

Some responders did have 9p24.1 alterations, but others did not. None of the responders had tumor cells positive for programmed death–ligand 1 (PD-L1), and only one responder had detectable PD-L2 expression in malignant cells.

Dr. Ansell and his colleagues described these findings in the Journal of Clinical Oncology.

The researchers evaluated nivolumab in a phase 2 trial (NCT02038933) of patients with relapsed/refractory DLBCL. Of the 121 patients, 87 had failed autologous hematopoietic stem cell transplant (HSCT) and 34 were ineligible for autologous HSCT. The patients received nivolumab at 3 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or study withdrawal.

HSCT failures

The patients who had failed HSCT had a median age of 62 years (range, 24-75 years). They had received a median of three prior systemic therapies (range, 1-11), and 28% were refractory to their most recent therapy.

About 40% of patients had germinal center B-cell–like (GCB) DLBCL, 32% had non-GCB disease, and data on disease subtype were missing for the rest of the group.

The patients received a median of four nivolumab doses (range, 1-44) and were followed for a median of 9 months (range, 0.1-25 months).

Nine patients (10%) achieved a response, and the median duration of response was 11 months. Responses occurred in patients with GCB and non-GCB DLBCL.

Three patients achieved a CR. Two of them were still on treatment and in CR at the data cutoff. Their responses had lasted 11 months and 14 months, respectively. The third complete responder did not progress on nivolumab but developed myelodysplastic syndrome, which was unrelated to the drug, and died.

Among all patients who had failed HSCT, the median progression-free survival was 1.9 months, and the median overall survival was 12.2 months.

Seven patients in this group were still receiving nivolumab at the data cutoff. Two of them were in CR, two had a partial response, and three had stable disease.

HSCT-ineligible group

The patients who were ineligible for HSCT had a median age of 68 years (range, 28-86 years). They had received a median of three prior systemic therapies (range, 1-7), and 59% were refractory to their most recent therapy.

About 56% of these patients had GCB DLBCL, 18% had non-GCB disease, and data on subtype were missing for the rest of the group.

The patients received a median of three nivolumab doses (range, 1-22) and were followed for a median of 6 months (range, 0.2-24 months). One patient (3%) achieved a partial response, which lasted 8.3 months.

The median progression-free survival in this group was 1.4 months, and the median overall survival was 5.8 months.

None of the patients in this group were still taking nivolumab at the data cutoff.

Biomarkers of response

Dr. Ansell and his colleagues were able to look for 9p24.1 alterations in archival tumor biopsy specimens from 74 patients. The team reported that 9p24.1 alterations were “infrequent,” but they were found in some responders.

Among the three complete responders, one patient had high-level 9p24.1 amplification, one had normal 9p24.1 copy number, and one did not have a biopsy available.

Among the seven patients who achieved a partial response, five had biopsy specimens. Three patients had low-level polysomy, one had copy gain, and one patient had normal 9p24.1.

None of the responders had PD-L1 expression in their tumor cells, but one complete responder had PD-L2–positive malignant cells.

Dr. Ansell and his colleagues wrote that the “biologic basis for response in the other two [complete responders] is unclear,” and the researchers were unable to assess associations between response and c-myc expression or double-hit lymphoma.

Safety

Of all 121 patients, 62% had a treatment-related adverse event (AE) and 24% had a grade 3/4–related AE.

The most common related AEs of any grade were nausea (17%), fatigue (17%), diarrhea (10%), neutropenia (7%), thrombocytopenia (6%), decreased appetite (6%), lipase increase (5%), rash (5%), and pyrexia (5%).

Four patients (3%) stopped taking nivolumab because of treatment-related AEs, including neutropenia, thrombocytopenia, diarrhea, pancreatitis, lipase increase, and psoriasiform dermatitis. There were no fatal treatment-related AEs.

This research was supported by Bristol-Myers Squibb and other groups. The study authors reported relationships with Bristol-Myers Squibb and other companies.

[email protected]

SOURCE: Ansell SM et al. J Clin Oncol. 2019 Jan 8. doi: 10.1200/JCO.18.00766.

Nivolumab may provide a benefit for a small group of patients with diffuse large B-cell lymphoma (DLBCL) who have failed a transplant or are ineligible for one, according to researchers.

Nivolumab produced a response in 10 of 121 DLBCL patients studied. Three patients achieved a complete response (CR) lasting 11 months or more.

Why this small group responded to nivolumab isn’t clear, according to Stephen M. Ansell, MD, PhD, of the Mayo Clinic in Rochester, Minn., and his colleagues.

Some responders did have 9p24.1 alterations, but others did not. None of the responders had tumor cells positive for programmed death–ligand 1 (PD-L1), and only one responder had detectable PD-L2 expression in malignant cells.

Dr. Ansell and his colleagues described these findings in the Journal of Clinical Oncology.

The researchers evaluated nivolumab in a phase 2 trial (NCT02038933) of patients with relapsed/refractory DLBCL. Of the 121 patients, 87 had failed autologous hematopoietic stem cell transplant (HSCT) and 34 were ineligible for autologous HSCT. The patients received nivolumab at 3 mg/kg every 2 weeks until disease progression, unacceptable toxicity, or study withdrawal.

HSCT failures

The patients who had failed HSCT had a median age of 62 years (range, 24-75 years). They had received a median of three prior systemic therapies (range, 1-11), and 28% were refractory to their most recent therapy.

About 40% of patients had germinal center B-cell–like (GCB) DLBCL, 32% had non-GCB disease, and data on disease subtype were missing for the rest of the group.

The patients received a median of four nivolumab doses (range, 1-44) and were followed for a median of 9 months (range, 0.1-25 months).

Nine patients (10%) achieved a response, and the median duration of response was 11 months. Responses occurred in patients with GCB and non-GCB DLBCL.

Three patients achieved a CR. Two of them were still on treatment and in CR at the data cutoff. Their responses had lasted 11 months and 14 months, respectively. The third complete responder did not progress on nivolumab but developed myelodysplastic syndrome, which was unrelated to the drug, and died.

Among all patients who had failed HSCT, the median progression-free survival was 1.9 months, and the median overall survival was 12.2 months.

Seven patients in this group were still receiving nivolumab at the data cutoff. Two of them were in CR, two had a partial response, and three had stable disease.

HSCT-ineligible group

The patients who were ineligible for HSCT had a median age of 68 years (range, 28-86 years). They had received a median of three prior systemic therapies (range, 1-7), and 59% were refractory to their most recent therapy.

About 56% of these patients had GCB DLBCL, 18% had non-GCB disease, and data on subtype were missing for the rest of the group.

The patients received a median of three nivolumab doses (range, 1-22) and were followed for a median of 6 months (range, 0.2-24 months). One patient (3%) achieved a partial response, which lasted 8.3 months.

The median progression-free survival in this group was 1.4 months, and the median overall survival was 5.8 months.

None of the patients in this group were still taking nivolumab at the data cutoff.

Biomarkers of response

Dr. Ansell and his colleagues were able to look for 9p24.1 alterations in archival tumor biopsy specimens from 74 patients. The team reported that 9p24.1 alterations were “infrequent,” but they were found in some responders.

Among the three complete responders, one patient had high-level 9p24.1 amplification, one had normal 9p24.1 copy number, and one did not have a biopsy available.

Among the seven patients who achieved a partial response, five had biopsy specimens. Three patients had low-level polysomy, one had copy gain, and one patient had normal 9p24.1.

None of the responders had PD-L1 expression in their tumor cells, but one complete responder had PD-L2–positive malignant cells.

Dr. Ansell and his colleagues wrote that the “biologic basis for response in the other two [complete responders] is unclear,” and the researchers were unable to assess associations between response and c-myc expression or double-hit lymphoma.

Safety

Of all 121 patients, 62% had a treatment-related adverse event (AE) and 24% had a grade 3/4–related AE.

The most common related AEs of any grade were nausea (17%), fatigue (17%), diarrhea (10%), neutropenia (7%), thrombocytopenia (6%), decreased appetite (6%), lipase increase (5%), rash (5%), and pyrexia (5%).

Four patients (3%) stopped taking nivolumab because of treatment-related AEs, including neutropenia, thrombocytopenia, diarrhea, pancreatitis, lipase increase, and psoriasiform dermatitis. There were no fatal treatment-related AEs.

This research was supported by Bristol-Myers Squibb and other groups. The study authors reported relationships with Bristol-Myers Squibb and other companies.

[email protected]

SOURCE: Ansell SM et al. J Clin Oncol. 2019 Jan 8. doi: 10.1200/JCO.18.00766.

A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.

The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.

“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”

The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.

A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.

In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.

In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.

Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.

Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.

The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).

Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.

“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”

The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.

SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.

A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.

The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.

“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”

The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.

A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.

In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.

In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.

Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.

Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.

The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).

Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.

“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”

The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.

SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.

A triplet combination of targeted agents ublituximab, umbralisib, and ibrutinib may be a safe and effective regimen for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and other B-cell malignancies, according to early study results.

The phase 1 trial had an overall response rate of 84% and a favorable safety profile, reported lead author Loretta J. Nastoupil, MD, of the University of Texas MD Anderson Cancer Center, Houston, and her colleagues. The results suggest that the regimen could eventually serve as a nonchemotherapeutic option for patients with B-cell malignancies.

“Therapeutic targeting of the B-cell receptor signaling pathway has revolutionized the management of B-cell lymphomas,” the investigators wrote in the Lancet Haematology. “Optimum combinations that result in longer periods of remission, possibly allowing for discontinuation of therapy, are needed.”

The present triplet combination included ublituximab, an anti-CD20 monoclonal antibody; ibrutinib, a Bruton tyrosine kinase inhibitor; and umbralisib, a phosphoinositide 3-kinase delta inhibitor.

A total of 46 patients with CLL/SLL or relapsed/refractory B-cell non-Hodgkin lymphoma received at least one dose of the combination in dose-escalation or dose-expansion study sections.

In the dose-escalation group (n = 24), ublituximab was given intravenously at 900 mg, ibrutinib was given orally at 420 mg for CLL and 560 mg for B-cell non-Hodgkin lymphoma, and umbralisib was given orally at three dose levels: 400 mg, 600 mg, and 800 mg.

In the dose-expansion group (n = 22), umbralisib was set at 800 mg while the other agents remained at the previous doses; treatment continued until intolerance or disease progression occurred. The investigators monitored efficacy and safety at defined intervals.

Results showed that 37 out of 44 evaluable patients (84%) had partial or complete responses to therapy.

Among the 22 CLL/SLL patients, there was a 100% overall response rate for both previously treated and untreated patients. Similarly, all three of the patients with marginal zone lymphoma responded, all six of the patients with mantle cell lymphoma responded, and five of seven patients with follicular lymphoma responded. However, only one of the six patients with diffuse large B-cell lymphoma had even a partial response.

The most common adverse events of any kind were diarrhea (59%), fatigue (50%), infusion-related reaction (43%), dizziness (37%), nausea (37%), and cough (35%). The most common grade 3 or higher adverse events were neutropenia (22%) and cellulitis (13%).

Serious adverse events were reported in 24% of patients; pneumonia, rash, sepsis, atrial fibrillation, and syncope occurred in two patients each; abdominal pain, pneumonitis, cellulitis, headache, skin infection, pleural effusion, upper gastrointestinal bleeding, pericardial effusion, weakness, and diarrhea occurred in one patient each. No adverse event–related deaths were reported.

“The findings of this study establish the tolerable safety profile of the ublituximab, umbralisib, and ibrutinib triplet regimen in chronic lymphocytic leukemia or small lymphocytic lymphoma and relapsed or refractory B-cell non-Hodgkin lymphoma,” the investigators wrote. “This triplet combination is expected to be investigated further in future clinical trials in different patient populations.”

The study was funded by TG Therapeutics. The authors reported financial relationships with TG Therapeutics and other companies.

SOURCE: Nastoupil LJ et al. Lancet Haematol. 2019 Feb;6(2):e100-9.

The Food and Drug Administration has approved a split-dosing regimen for daratumumab (Darzalex) in patients with multiple myeloma, allowing the first infusion to be split over 2 days.

FDA approval is based on results from the global, multi-arm, phase 1b EQUULEUS (MMY1001) trial, which evaluated daratumumab in combination with a variety of treatment regimens. Splitting the first infusion over 2 consecutive days reduced the duration of the infusion and resulted in a similar rate of infusion site reactions; concentrations were similar at the end of weekly dosing in patients who received the first infusion at once or over a 2-day period.

The adverse events reported in EQUULEUS (MMY1001) were largely similar to those seen in previous trials; the most common adverse events include infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, and upper respiratory tract infection.

The approval providers “added flexibility for how patients may receive initial treatment,” Craig Tendler, MD, vice president of clinical development and global medical affairs at Janssen Research & Development, said in a statement.

[email protected]

The Food and Drug Administration has approved a split-dosing regimen for daratumumab (Darzalex) in patients with multiple myeloma, allowing the first infusion to be split over 2 days.

FDA approval is based on results from the global, multi-arm, phase 1b EQUULEUS (MMY1001) trial, which evaluated daratumumab in combination with a variety of treatment regimens. Splitting the first infusion over 2 consecutive days reduced the duration of the infusion and resulted in a similar rate of infusion site reactions; concentrations were similar at the end of weekly dosing in patients who received the first infusion at once or over a 2-day period.

The adverse events reported in EQUULEUS (MMY1001) were largely similar to those seen in previous trials; the most common adverse events include infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, and upper respiratory tract infection.

The approval providers “added flexibility for how patients may receive initial treatment,” Craig Tendler, MD, vice president of clinical development and global medical affairs at Janssen Research & Development, said in a statement.

[email protected]

The Food and Drug Administration has approved a split-dosing regimen for daratumumab (Darzalex) in patients with multiple myeloma, allowing the first infusion to be split over 2 days.

FDA approval is based on results from the global, multi-arm, phase 1b EQUULEUS (MMY1001) trial, which evaluated daratumumab in combination with a variety of treatment regimens. Splitting the first infusion over 2 consecutive days reduced the duration of the infusion and resulted in a similar rate of infusion site reactions; concentrations were similar at the end of weekly dosing in patients who received the first infusion at once or over a 2-day period.

The adverse events reported in EQUULEUS (MMY1001) were largely similar to those seen in previous trials; the most common adverse events include infusion reactions, neutropenia, thrombocytopenia, fatigue, nausea, diarrhea, constipation, vomiting, muscle spasms, arthralgia, back pain, pyrexia, chills, dizziness, insomnia, cough, dyspnea, peripheral edema, peripheral sensory neuropathy, and upper respiratory tract infection.

The approval providers “added flexibility for how patients may receive initial treatment,” Craig Tendler, MD, vice president of clinical development and global medical affairs at Janssen Research & Development, said in a statement.

[email protected]

While optimal treatment for grade 3A follicular lymphoma remains in question, either anthracycline-based chemotherapy or bendamustine appear to be preferable to cyclophosphamide, vincristine, and prednisone (CVP), results of a recent analysis suggest.

Time to progression with anthracycline-based chemotherapy was superior to that of CVP in the retrospective, multicenter study.

At the same time, clinical outcomes were comparable between anthracycline-based chemotherapy and bendamustine, according to Nirav N. Shah, MD, of the Medical College of Wisconsin, Milwaukee, and his coinvestigators.

“Both remain appropriate frontline options for this patient population,” Dr. Shah and his colleagues wrote in Clinical Lymphoma, Myeloma & Leukemia.

Frontline therapy for follicular lymphoma has evolved, and recently shifted toward bendamustine-based chemotherapy regimens in light of two large randomized trials, according to the investigators. However, optimal therapy – specifically for grade 3A follicular lymphoma – has been debated for more than 20 years, they added.

“While some approach it as an aggressive malignancy, others treat it as an indolent lymphoma,” they wrote.

Accordingly, Dr. Shah and his colleagues sought to evaluate treatment outcomes with these regimens in 103 advanced stage 3/4 follicular lymphoma patients from six centers seen over a 10-year period.

Of those patients, 65 had received anthracycline-based chemotherapy, 30 received bendamustine, and 8 received CVP. All received either rituximab or ofatumumab in combination with the chemotherapy, and about one-third went on to receive maintenance treatment with one of those two anti-CD20 antibodies.

The proportion of patients not experiencing disease progression at 24 months from the initiation of treatment was significantly different between arms, at 72% for those receiving anthracyclines, 79% for bendamustine, and 50% for CVP (P = .01).

Patients who received CVP had a significantly poorer time-to-progression outcomes versus anthracycline-based chemotherapy, an adjusted analysis showed (hazard ratio, 3.22; 95% confidence interval, 1.26-8.25; P = .01), while by contrast, there was no significant difference between bendamustine and anthracyclines on this endpoint.

Progression-free survival was likewise worse for CVP compared with anthracycline-based chemotherapy, but there was no significant difference in overall survival for either CVP or bendamustine compared with anthracycline-based chemotherapy, the investigators said.

The 5-year overall survival was estimated to be 82% for anthracycline-based chemotherapy, 74% for bendamustine, and 58% for CVP (P = .23).

Optimal treatment of grade 3A follicular lymphoma remains controversial despite these findings, the investigators noted.

“Unfortunately, this specific histology was excluded from pivotal trials comparing anthracycline-based chemotherapy to bendamustine, leaving the question of optimal frontline treatment unanswered in this subset,” they wrote.

The situation could change with a subgroup analysis of GALLIUM, which might provide some prospective data for this histology. Beyond that, it would be helpful to have prospective, randomized studies specifically enrolling grade 3A disease, Dr. Shah and his coauthors wrote.

Dr. Shah reported disclosures related to Exelixis, Oncosec, Geron, Jazz, Kite, Juno, and Lentigen Technology. Coauthors provided disclosures related to Sanofi-Genzyme, Celgene, Takeda, Otsuka, Spectrum, Merck, and Astellas, among others.

SOURCE: Shah NN et al. Clin Lymphoma Myeloma Leuk. 2019 Feb;19(2):95-102.

While optimal treatment for grade 3A follicular lymphoma remains in question, either anthracycline-based chemotherapy or bendamustine appear to be preferable to cyclophosphamide, vincristine, and prednisone (CVP), results of a recent analysis suggest.

Time to progression with anthracycline-based chemotherapy was superior to that of CVP in the retrospective, multicenter study.

At the same time, clinical outcomes were comparable between anthracycline-based chemotherapy and bendamustine, according to Nirav N. Shah, MD, of the Medical College of Wisconsin, Milwaukee, and his coinvestigators.

“Both remain appropriate frontline options for this patient population,” Dr. Shah and his colleagues wrote in Clinical Lymphoma, Myeloma & Leukemia.

Frontline therapy for follicular lymphoma has evolved, and recently shifted toward bendamustine-based chemotherapy regimens in light of two large randomized trials, according to the investigators. However, optimal therapy – specifically for grade 3A follicular lymphoma – has been debated for more than 20 years, they added.

“While some approach it as an aggressive malignancy, others treat it as an indolent lymphoma,” they wrote.

Accordingly, Dr. Shah and his colleagues sought to evaluate treatment outcomes with these regimens in 103 advanced stage 3/4 follicular lymphoma patients from six centers seen over a 10-year period.

Of those patients, 65 had received anthracycline-based chemotherapy, 30 received bendamustine, and 8 received CVP. All received either rituximab or ofatumumab in combination with the chemotherapy, and about one-third went on to receive maintenance treatment with one of those two anti-CD20 antibodies.

The proportion of patients not experiencing disease progression at 24 months from the initiation of treatment was significantly different between arms, at 72% for those receiving anthracyclines, 79% for bendamustine, and 50% for CVP (P = .01).

Patients who received CVP had a significantly poorer time-to-progression outcomes versus anthracycline-based chemotherapy, an adjusted analysis showed (hazard ratio, 3.22; 95% confidence interval, 1.26-8.25; P = .01), while by contrast, there was no significant difference between bendamustine and anthracyclines on this endpoint.

Progression-free survival was likewise worse for CVP compared with anthracycline-based chemotherapy, but there was no significant difference in overall survival for either CVP or bendamustine compared with anthracycline-based chemotherapy, the investigators said.

The 5-year overall survival was estimated to be 82% for anthracycline-based chemotherapy, 74% for bendamustine, and 58% for CVP (P = .23).

Optimal treatment of grade 3A follicular lymphoma remains controversial despite these findings, the investigators noted.

“Unfortunately, this specific histology was excluded from pivotal trials comparing anthracycline-based chemotherapy to bendamustine, leaving the question of optimal frontline treatment unanswered in this subset,” they wrote.

The situation could change with a subgroup analysis of GALLIUM, which might provide some prospective data for this histology. Beyond that, it would be helpful to have prospective, randomized studies specifically enrolling grade 3A disease, Dr. Shah and his coauthors wrote.

Dr. Shah reported disclosures related to Exelixis, Oncosec, Geron, Jazz, Kite, Juno, and Lentigen Technology. Coauthors provided disclosures related to Sanofi-Genzyme, Celgene, Takeda, Otsuka, Spectrum, Merck, and Astellas, among others.

SOURCE: Shah NN et al. Clin Lymphoma Myeloma Leuk. 2019 Feb;19(2):95-102.

While optimal treatment for grade 3A follicular lymphoma remains in question, either anthracycline-based chemotherapy or bendamustine appear to be preferable to cyclophosphamide, vincristine, and prednisone (CVP), results of a recent analysis suggest.

Time to progression with anthracycline-based chemotherapy was superior to that of CVP in the retrospective, multicenter study.

At the same time, clinical outcomes were comparable between anthracycline-based chemotherapy and bendamustine, according to Nirav N. Shah, MD, of the Medical College of Wisconsin, Milwaukee, and his coinvestigators.

“Both remain appropriate frontline options for this patient population,” Dr. Shah and his colleagues wrote in Clinical Lymphoma, Myeloma & Leukemia.

Frontline therapy for follicular lymphoma has evolved, and recently shifted toward bendamustine-based chemotherapy regimens in light of two large randomized trials, according to the investigators. However, optimal therapy – specifically for grade 3A follicular lymphoma – has been debated for more than 20 years, they added.

“While some approach it as an aggressive malignancy, others treat it as an indolent lymphoma,” they wrote.

Accordingly, Dr. Shah and his colleagues sought to evaluate treatment outcomes with these regimens in 103 advanced stage 3/4 follicular lymphoma patients from six centers seen over a 10-year period.

Of those patients, 65 had received anthracycline-based chemotherapy, 30 received bendamustine, and 8 received CVP. All received either rituximab or ofatumumab in combination with the chemotherapy, and about one-third went on to receive maintenance treatment with one of those two anti-CD20 antibodies.

The proportion of patients not experiencing disease progression at 24 months from the initiation of treatment was significantly different between arms, at 72% for those receiving anthracyclines, 79% for bendamustine, and 50% for CVP (P = .01).

Patients who received CVP had a significantly poorer time-to-progression outcomes versus anthracycline-based chemotherapy, an adjusted analysis showed (hazard ratio, 3.22; 95% confidence interval, 1.26-8.25; P = .01), while by contrast, there was no significant difference between bendamustine and anthracyclines on this endpoint.

Progression-free survival was likewise worse for CVP compared with anthracycline-based chemotherapy, but there was no significant difference in overall survival for either CVP or bendamustine compared with anthracycline-based chemotherapy, the investigators said.

The 5-year overall survival was estimated to be 82% for anthracycline-based chemotherapy, 74% for bendamustine, and 58% for CVP (P = .23).

Optimal treatment of grade 3A follicular lymphoma remains controversial despite these findings, the investigators noted.

“Unfortunately, this specific histology was excluded from pivotal trials comparing anthracycline-based chemotherapy to bendamustine, leaving the question of optimal frontline treatment unanswered in this subset,” they wrote.

The situation could change with a subgroup analysis of GALLIUM, which might provide some prospective data for this histology. Beyond that, it would be helpful to have prospective, randomized studies specifically enrolling grade 3A disease, Dr. Shah and his coauthors wrote.

Dr. Shah reported disclosures related to Exelixis, Oncosec, Geron, Jazz, Kite, Juno, and Lentigen Technology. Coauthors provided disclosures related to Sanofi-Genzyme, Celgene, Takeda, Otsuka, Spectrum, Merck, and Astellas, among others.

SOURCE: Shah NN et al. Clin Lymphoma Myeloma Leuk. 2019 Feb;19(2):95-102.

The three-drug combination of ibrutinib, high-dose methotrexate (HD-MTX), and rituximab showed positive safety and clinical outcomes in patients with recurrent/refractory primary/secondary CNS lymphoma, according to results from a phase 1b trial.

Ibrutinib has already shown single-agent activity in recurrent/refractory CNS lymphoma, Christian Grommes, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues, wrote in Blood. “The primary objective was to determine the maximum tolerated dose of ibrutinib in combination with HD-MTX alone and ibrutinib in combination with HD-MTX and rituximab.”

With respect to ibrutinib dosing, the initial cohort was started at 560 mg daily, which was increased to 840 mg daily in successive cohorts using a 3+3 design. HD-MTX was administered every 2 weeks at 3.5 g/m² for a total of eight infusions, or four cycles, with each cycle lasting of 28 days.

After no dose-limiting adverse effects were seen with the ibrutinib-MTX combination, the researchers added rituximab at 500 mg/m² every 2 weeks, for a total of eight infusions, which completed the induction phase. The three-agent induction therapy was followed by daily ibrutinib monotherapy, which was maintained until discontinuation caused by malignancy progression, intolerable adverse events, or death.

“To minimize the risk of adverse events, we held ibrutinib on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after MTX clearance,” they wrote.

After analysis, Dr. Grommes and his colleagues reported that no dose-limiting or grade 5 toxicities were detected. At a median follow-up of 19.7 months, they saw an 80% overall response rate in study patients treated with combination therapy. The median progression free survival for all 15 patients was 9.2 months and the median overall survival was not reached, with 11 of 15 patients alive.

The researchers proposed an 840-mg dose of ibrutinib for future studies.

The most frequent adverse events were lymphopenia, thrombocytopenia, anemia, and transaminase elevations. No fungal infections were seen during the study.

The researchers noted that two key limitations of the study were the nonrandomized design and small sample size. As a result, they reported that the degree of ibrutinib-specific activity in the three-drug combination remains unknown.

The study was supported by grant funding from Pharmacyclics to Memorial Sloan Kettering. The authors reported financial ties to AstraZeneca, Bristol-Myers Squibb, BTH, Kite Pharma, Pfizer, and others.

SOURCE: Grommes C et al. Blood. 2019;133(5):436-45.

The three-drug combination of ibrutinib, high-dose methotrexate (HD-MTX), and rituximab showed positive safety and clinical outcomes in patients with recurrent/refractory primary/secondary CNS lymphoma, according to results from a phase 1b trial.

Ibrutinib has already shown single-agent activity in recurrent/refractory CNS lymphoma, Christian Grommes, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues, wrote in Blood. “The primary objective was to determine the maximum tolerated dose of ibrutinib in combination with HD-MTX alone and ibrutinib in combination with HD-MTX and rituximab.”

With respect to ibrutinib dosing, the initial cohort was started at 560 mg daily, which was increased to 840 mg daily in successive cohorts using a 3+3 design. HD-MTX was administered every 2 weeks at 3.5 g/m² for a total of eight infusions, or four cycles, with each cycle lasting of 28 days.

After no dose-limiting adverse effects were seen with the ibrutinib-MTX combination, the researchers added rituximab at 500 mg/m² every 2 weeks, for a total of eight infusions, which completed the induction phase. The three-agent induction therapy was followed by daily ibrutinib monotherapy, which was maintained until discontinuation caused by malignancy progression, intolerable adverse events, or death.

“To minimize the risk of adverse events, we held ibrutinib on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after MTX clearance,” they wrote.

After analysis, Dr. Grommes and his colleagues reported that no dose-limiting or grade 5 toxicities were detected. At a median follow-up of 19.7 months, they saw an 80% overall response rate in study patients treated with combination therapy. The median progression free survival for all 15 patients was 9.2 months and the median overall survival was not reached, with 11 of 15 patients alive.

The researchers proposed an 840-mg dose of ibrutinib for future studies.

The most frequent adverse events were lymphopenia, thrombocytopenia, anemia, and transaminase elevations. No fungal infections were seen during the study.

The researchers noted that two key limitations of the study were the nonrandomized design and small sample size. As a result, they reported that the degree of ibrutinib-specific activity in the three-drug combination remains unknown.

The study was supported by grant funding from Pharmacyclics to Memorial Sloan Kettering. The authors reported financial ties to AstraZeneca, Bristol-Myers Squibb, BTH, Kite Pharma, Pfizer, and others.

SOURCE: Grommes C et al. Blood. 2019;133(5):436-45.

The three-drug combination of ibrutinib, high-dose methotrexate (HD-MTX), and rituximab showed positive safety and clinical outcomes in patients with recurrent/refractory primary/secondary CNS lymphoma, according to results from a phase 1b trial.

Ibrutinib has already shown single-agent activity in recurrent/refractory CNS lymphoma, Christian Grommes, MD, of Memorial Sloan Kettering Cancer Center in New York, and his colleagues, wrote in Blood. “The primary objective was to determine the maximum tolerated dose of ibrutinib in combination with HD-MTX alone and ibrutinib in combination with HD-MTX and rituximab.”

With respect to ibrutinib dosing, the initial cohort was started at 560 mg daily, which was increased to 840 mg daily in successive cohorts using a 3+3 design. HD-MTX was administered every 2 weeks at 3.5 g/m² for a total of eight infusions, or four cycles, with each cycle lasting of 28 days.

After no dose-limiting adverse effects were seen with the ibrutinib-MTX combination, the researchers added rituximab at 500 mg/m² every 2 weeks, for a total of eight infusions, which completed the induction phase. The three-agent induction therapy was followed by daily ibrutinib monotherapy, which was maintained until discontinuation caused by malignancy progression, intolerable adverse events, or death.

“To minimize the risk of adverse events, we held ibrutinib on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after MTX clearance,” they wrote.

After analysis, Dr. Grommes and his colleagues reported that no dose-limiting or grade 5 toxicities were detected. At a median follow-up of 19.7 months, they saw an 80% overall response rate in study patients treated with combination therapy. The median progression free survival for all 15 patients was 9.2 months and the median overall survival was not reached, with 11 of 15 patients alive.

The researchers proposed an 840-mg dose of ibrutinib for future studies.

The most frequent adverse events were lymphopenia, thrombocytopenia, anemia, and transaminase elevations. No fungal infections were seen during the study.

The researchers noted that two key limitations of the study were the nonrandomized design and small sample size. As a result, they reported that the degree of ibrutinib-specific activity in the three-drug combination remains unknown.

The study was supported by grant funding from Pharmacyclics to Memorial Sloan Kettering. The authors reported financial ties to AstraZeneca, Bristol-Myers Squibb, BTH, Kite Pharma, Pfizer, and others.

SOURCE: Grommes C et al. Blood. 2019;133(5):436-45.

Daratumumab is safe but ineffective for the treatment of patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and CD38 expression of at least 50%, according to findings from a recent phase 2 trial.

Unfortunately, the study met headwinds early on, when initial screening of 112 patients with available tumor samples showed that only about half (56%) had CD38 expression of at least 50%, reported lead author Giles Salles, MD, PhD, of Claude Bernard University in Lyon, France, and his colleagues. The cutoff was based on preclinical models, suggesting that daratumumab-induced cytotoxicity depends on a high level of CD38 expression.

“Only 36 [patients] were eligible for study enrollment, questioning the generalizability of the study population,” the investigators wrote in Clinical Lymphoma, Myeloma & Leukemia.

Of these 36 patients, 15 had diffuse large B-cell lymphoma (DLBCL), 16 had follicular lymphoma (FL), and 5 had mantle cell lymphoma (MCL). Median CD38 expression was 70%. Patients were given 16 mg/kg of IV daratumumab once a week for two cycles, then every 2 weeks for four cycles, and finally on a monthly basis. Cycles were 28 days long. The primary endpoint was overall response rate. Safety and pharmacokinetics were also evaluated.

Results were generally disappointing, with ORR occurring in two patients (12.5%) with FL and one patient (6.7%) with DLBCL. No patients with MCL responded before the study was terminated. On a more encouraging note, 10 of 16 patients with FL maintained stable disease.

“All 16 patients in the FL cohort had progressed/relapsed on their prior treatment regimen; therefore, the maintenance of stable disease in the FL cohort may suggest some clinical benefit of daratumumab in this subset of NHL,” the investigators wrote.

Pharmacokinetics and safety data were similar to those from multiple myeloma studies of daratumumab; no new safety signals or instances of immunogenicity were encountered. The most common grade 3 or higher treatment-related adverse event was thrombocytopenia, which occurred in 11.1% of patients. Infusion-related reactions occurred in 72.2% of patients, but none were grade 4 and only three reactions were grade 3.

The investigators suggested that daratumumab may still play a role in NHL treatment, but not as a single agent.

“It is possible that daratumumab-based combination therapy would have allowed for more responses to be achieved within the current study,” the investigators wrote. “NHL is an extremely heterogeneous disease and the identification of predictive biomarkers and molecular genetics may provide new personalized therapies.”

The study was funded by Janssen Research & Development; two study authors reported employment by Janssen. Others reported financial ties to Janssen, Celgene, Roche, Gilead, Novartis, Amgen, and others.

SOURCE: Salles G et al. Clin Lymphoma Myeloma Leuk. 2019 Jan 2. doi: 10.1016/j.clml.2018.12.013.

Daratumumab is safe but ineffective for the treatment of patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and CD38 expression of at least 50%, according to findings from a recent phase 2 trial.

Unfortunately, the study met headwinds early on, when initial screening of 112 patients with available tumor samples showed that only about half (56%) had CD38 expression of at least 50%, reported lead author Giles Salles, MD, PhD, of Claude Bernard University in Lyon, France, and his colleagues. The cutoff was based on preclinical models, suggesting that daratumumab-induced cytotoxicity depends on a high level of CD38 expression.

“Only 36 [patients] were eligible for study enrollment, questioning the generalizability of the study population,” the investigators wrote in Clinical Lymphoma, Myeloma & Leukemia.

Of these 36 patients, 15 had diffuse large B-cell lymphoma (DLBCL), 16 had follicular lymphoma (FL), and 5 had mantle cell lymphoma (MCL). Median CD38 expression was 70%. Patients were given 16 mg/kg of IV daratumumab once a week for two cycles, then every 2 weeks for four cycles, and finally on a monthly basis. Cycles were 28 days long. The primary endpoint was overall response rate. Safety and pharmacokinetics were also evaluated.

Results were generally disappointing, with ORR occurring in two patients (12.5%) with FL and one patient (6.7%) with DLBCL. No patients with MCL responded before the study was terminated. On a more encouraging note, 10 of 16 patients with FL maintained stable disease.

“All 16 patients in the FL cohort had progressed/relapsed on their prior treatment regimen; therefore, the maintenance of stable disease in the FL cohort may suggest some clinical benefit of daratumumab in this subset of NHL,” the investigators wrote.

Pharmacokinetics and safety data were similar to those from multiple myeloma studies of daratumumab; no new safety signals or instances of immunogenicity were encountered. The most common grade 3 or higher treatment-related adverse event was thrombocytopenia, which occurred in 11.1% of patients. Infusion-related reactions occurred in 72.2% of patients, but none were grade 4 and only three reactions were grade 3.

The investigators suggested that daratumumab may still play a role in NHL treatment, but not as a single agent.

“It is possible that daratumumab-based combination therapy would have allowed for more responses to be achieved within the current study,” the investigators wrote. “NHL is an extremely heterogeneous disease and the identification of predictive biomarkers and molecular genetics may provide new personalized therapies.”

The study was funded by Janssen Research & Development; two study authors reported employment by Janssen. Others reported financial ties to Janssen, Celgene, Roche, Gilead, Novartis, Amgen, and others.

SOURCE: Salles G et al. Clin Lymphoma Myeloma Leuk. 2019 Jan 2. doi: 10.1016/j.clml.2018.12.013.

Daratumumab is safe but ineffective for the treatment of patients with relapsed or refractory non-Hodgkin lymphoma (NHL) and CD38 expression of at least 50%, according to findings from a recent phase 2 trial.

Unfortunately, the study met headwinds early on, when initial screening of 112 patients with available tumor samples showed that only about half (56%) had CD38 expression of at least 50%, reported lead author Giles Salles, MD, PhD, of Claude Bernard University in Lyon, France, and his colleagues. The cutoff was based on preclinical models, suggesting that daratumumab-induced cytotoxicity depends on a high level of CD38 expression.

“Only 36 [patients] were eligible for study enrollment, questioning the generalizability of the study population,” the investigators wrote in Clinical Lymphoma, Myeloma & Leukemia.

Of these 36 patients, 15 had diffuse large B-cell lymphoma (DLBCL), 16 had follicular lymphoma (FL), and 5 had mantle cell lymphoma (MCL). Median CD38 expression was 70%. Patients were given 16 mg/kg of IV daratumumab once a week for two cycles, then every 2 weeks for four cycles, and finally on a monthly basis. Cycles were 28 days long. The primary endpoint was overall response rate. Safety and pharmacokinetics were also evaluated.

Results were generally disappointing, with ORR occurring in two patients (12.5%) with FL and one patient (6.7%) with DLBCL. No patients with MCL responded before the study was terminated. On a more encouraging note, 10 of 16 patients with FL maintained stable disease.

“All 16 patients in the FL cohort had progressed/relapsed on their prior treatment regimen; therefore, the maintenance of stable disease in the FL cohort may suggest some clinical benefit of daratumumab in this subset of NHL,” the investigators wrote.

Pharmacokinetics and safety data were similar to those from multiple myeloma studies of daratumumab; no new safety signals or instances of immunogenicity were encountered. The most common grade 3 or higher treatment-related adverse event was thrombocytopenia, which occurred in 11.1% of patients. Infusion-related reactions occurred in 72.2% of patients, but none were grade 4 and only three reactions were grade 3.

The investigators suggested that daratumumab may still play a role in NHL treatment, but not as a single agent.

“It is possible that daratumumab-based combination therapy would have allowed for more responses to be achieved within the current study,” the investigators wrote. “NHL is an extremely heterogeneous disease and the identification of predictive biomarkers and molecular genetics may provide new personalized therapies.”

The study was funded by Janssen Research & Development; two study authors reported employment by Janssen. Others reported financial ties to Janssen, Celgene, Roche, Gilead, Novartis, Amgen, and others.

SOURCE: Salles G et al. Clin Lymphoma Myeloma Leuk. 2019 Jan 2. doi: 10.1016/j.clml.2018.12.013.

Intensity of BCL2 expression, and to a lesser extent expression of t(14;18), may help distinguish common and indolent cutaneous lymphomas from poorer-prognosis cutaneous lesions secondary to systemic follicular lymphomas, results of a recent investigation show.

Strong expression of BCL2 was almost always associated with secondary cutaneous follicular lymphoma (SCFL), and infrequently associated with primary cutaneous follicular center-cell lymphoma (PCFCL), according to the study results.

The translocation t(14;18) was likewise linked to secondary lesions, occurring less frequently in PCFCL in the study, reported recently in the Journal of Cutaneous Pathology.

“BCL2 expression intensity is the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds,” said Ramon M. Pujol, MD, PhD, of Hospital del Mar, Barcelona, Spain, and colleagues.

One of the main cutaneous B-cell lymphoma subtypes, PCFCL is marked by frequent relapses, but little incidence of systemic spread, meaning that conservative, skin-based therapies are usually warranted. By contrast, patients with SCFLs have a poor prognosis and may require systemic therapy, the investigators noted in their report.

Previous investigations have yielded conflicting results on the role of BCL2 expression, CD10 expression, and presence of t(14;18) translocation in distinguishing PCFCL from SCFL.

While early studies suggested most PCFCLs were negative for these markers, some recent reports suggested BCL positivity in PCFCLs is as high as 86%, the investigators said.

Accordingly, Dr. Pujol and colleagues evaluated clinicopathologic and genetic features in a large series of patients, including 59 with PCFCL and 22 with SCFL.

Significant BCL2 expression was seen in 69% of PCFCLs and in 100% of SCFLs (P = .003) in this patient series; however, when looking at BCL2 intensity, investigators found strong expression almost exclusively in SCFL. Strong expression was seen in 46% of those patients with secondary lymphomas, versus just 4%, or two cases, in the PCFCL group (P = .001).

The t(14;18) translocation was seen in 64% of SCFLs and only 9.1% of PCFCLs (P = .001).

Similar to what was seen for BCL2, expression of CD10 was observed in 66% of PCFCLs and 91% of SCFLs, and again, intensity differences mattered. Strong CD10 expression was seen in 62% of secondary lymphomas and 16% of PCFCLs (P = .01). But the high number of positive PCFCLs made this marker less useful than BCL2, the investigators said.

“We believe that differences in BCL2 and CD10 expression between our results and older previous studies could reflect the improvement of antigen retrieval laboratory techniques,” they said.

The investigators did not report disclosures related to the research.

SOURCE: Servitje O et al. J Cutan Pathol. 2019;46:182-9.

Intensity of BCL2 expression, and to a lesser extent expression of t(14;18), may help distinguish common and indolent cutaneous lymphomas from poorer-prognosis cutaneous lesions secondary to systemic follicular lymphomas, results of a recent investigation show.

Strong expression of BCL2 was almost always associated with secondary cutaneous follicular lymphoma (SCFL), and infrequently associated with primary cutaneous follicular center-cell lymphoma (PCFCL), according to the study results.

The translocation t(14;18) was likewise linked to secondary lesions, occurring less frequently in PCFCL in the study, reported recently in the Journal of Cutaneous Pathology.

“BCL2 expression intensity is the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds,” said Ramon M. Pujol, MD, PhD, of Hospital del Mar, Barcelona, Spain, and colleagues.

One of the main cutaneous B-cell lymphoma subtypes, PCFCL is marked by frequent relapses, but little incidence of systemic spread, meaning that conservative, skin-based therapies are usually warranted. By contrast, patients with SCFLs have a poor prognosis and may require systemic therapy, the investigators noted in their report.

Previous investigations have yielded conflicting results on the role of BCL2 expression, CD10 expression, and presence of t(14;18) translocation in distinguishing PCFCL from SCFL.

While early studies suggested most PCFCLs were negative for these markers, some recent reports suggested BCL positivity in PCFCLs is as high as 86%, the investigators said.

Accordingly, Dr. Pujol and colleagues evaluated clinicopathologic and genetic features in a large series of patients, including 59 with PCFCL and 22 with SCFL.

Significant BCL2 expression was seen in 69% of PCFCLs and in 100% of SCFLs (P = .003) in this patient series; however, when looking at BCL2 intensity, investigators found strong expression almost exclusively in SCFL. Strong expression was seen in 46% of those patients with secondary lymphomas, versus just 4%, or two cases, in the PCFCL group (P = .001).

The t(14;18) translocation was seen in 64% of SCFLs and only 9.1% of PCFCLs (P = .001).

Similar to what was seen for BCL2, expression of CD10 was observed in 66% of PCFCLs and 91% of SCFLs, and again, intensity differences mattered. Strong CD10 expression was seen in 62% of secondary lymphomas and 16% of PCFCLs (P = .01). But the high number of positive PCFCLs made this marker less useful than BCL2, the investigators said.

“We believe that differences in BCL2 and CD10 expression between our results and older previous studies could reflect the improvement of antigen retrieval laboratory techniques,” they said.

The investigators did not report disclosures related to the research.

SOURCE: Servitje O et al. J Cutan Pathol. 2019;46:182-9.

Intensity of BCL2 expression, and to a lesser extent expression of t(14;18), may help distinguish common and indolent cutaneous lymphomas from poorer-prognosis cutaneous lesions secondary to systemic follicular lymphomas, results of a recent investigation show.

Strong expression of BCL2 was almost always associated with secondary cutaneous follicular lymphoma (SCFL), and infrequently associated with primary cutaneous follicular center-cell lymphoma (PCFCL), according to the study results.

The translocation t(14;18) was likewise linked to secondary lesions, occurring less frequently in PCFCL in the study, reported recently in the Journal of Cutaneous Pathology.

“BCL2 expression intensity is the single most valuable clue in differentiating PCFCL from SCFL cases on histopathological grounds,” said Ramon M. Pujol, MD, PhD, of Hospital del Mar, Barcelona, Spain, and colleagues.

One of the main cutaneous B-cell lymphoma subtypes, PCFCL is marked by frequent relapses, but little incidence of systemic spread, meaning that conservative, skin-based therapies are usually warranted. By contrast, patients with SCFLs have a poor prognosis and may require systemic therapy, the investigators noted in their report.

Previous investigations have yielded conflicting results on the role of BCL2 expression, CD10 expression, and presence of t(14;18) translocation in distinguishing PCFCL from SCFL.

While early studies suggested most PCFCLs were negative for these markers, some recent reports suggested BCL positivity in PCFCLs is as high as 86%, the investigators said.

Accordingly, Dr. Pujol and colleagues evaluated clinicopathologic and genetic features in a large series of patients, including 59 with PCFCL and 22 with SCFL.

Significant BCL2 expression was seen in 69% of PCFCLs and in 100% of SCFLs (P = .003) in this patient series; however, when looking at BCL2 intensity, investigators found strong expression almost exclusively in SCFL. Strong expression was seen in 46% of those patients with secondary lymphomas, versus just 4%, or two cases, in the PCFCL group (P = .001).

The t(14;18) translocation was seen in 64% of SCFLs and only 9.1% of PCFCLs (P = .001).

Similar to what was seen for BCL2, expression of CD10 was observed in 66% of PCFCLs and 91% of SCFLs, and again, intensity differences mattered. Strong CD10 expression was seen in 62% of secondary lymphomas and 16% of PCFCLs (P = .01). But the high number of positive PCFCLs made this marker less useful than BCL2, the investigators said.

“We believe that differences in BCL2 and CD10 expression between our results and older previous studies could reflect the improvement of antigen retrieval laboratory techniques,” they said.

The investigators did not report disclosures related to the research.

SOURCE: Servitje O et al. J Cutan Pathol. 2019;46:182-9.