Lymphoma & Plasma Cell Disorders

A retrospective study suggests a four-drug regimen can be effective salvage therapy for patients with relapsed or refractory classical Hodgkin lymphoma.

The regimen – brentuximab vedotin plus ifosfamide, gemcitabine, and vinorelbine (BV-IGEV) – produced responses in 27 of 28 patients studied, allowing them to undergo autologous hematopoietic stem cell transplant (HSCT).

After HSCT, the estimated 2-year progression-free survival (PFS) was 87.1% and the overall survival (OS) was 73.5%.

Though this study was limited by its small population and retrospective nature, the results “warrant further investigation,” according to Khadega A. Abuelgasim, MD, of King Abdullah International Medical Research Center in Riyadh, Saudi Arabia, and colleagues.

The researchers reported the results in a letter to Bone Marrow Transplantation.

The study included 28 patients with classical Hodgkin lymphoma, 15 of them male. The patients’ median age at HSCT was 25 years (range, 15-49 years). Twenty patients (71%) had constitutional symptoms at diagnosis, and eight (29%) had bulky disease.

Twenty-three patients (82%) received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline therapy, and four (14%) received ABVD followed by escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. One patient received a different frontline regimen.

The median time to relapse was 7.9 months (range, 1.9-133 months), and 12 patients (43%) were refractory to frontline treatment.

Half of patients (n = 14) received BV-IGEV as first salvage. The regimen was given as follows: ifosfamide at 2,000 mg/m² on days 1-4, gemcitabine at 800 mg/m² on days 1 and 4, vinorelbine at 20 mg/m² on day 1, prednisolone at 100 mg on days 1-4, and BV at a dose of 1.8 mg/kg on day 1 of each 3-week IGEV course.

All patients received at least two cycles of BV-IGEV and were assessed for response after one or two cycles. The median follow-up was 17 months (range, 0-65 months).

Twenty patients (71%) had a complete metabolic response to BV-IGEV, seven (25%) had a partial metabolic response, and one patient (4%) had stable disease. The patient with stable disease went on to receive another salvage regimen and achieved a partial response to that regimen.

The most common adverse events during BV-IGEV treatment were grade 3-4 neutropenia (n = 27; 96%) and thrombocytopenia (n = 25; 89%). Febrile neutropenia was also common (n = 16; 57%), as were mucositis (n = 6; 21%) and diarrhea (n = 6; 21%). Six patients had a reduction in BV dose because of an adverse event.

All patients underwent autologous HSCT. They received carmustine, etoposide, cytarabine, and melphalan as conditioning beforehand, and 18 patients (64%) received consolidative BV after transplant.

PFS and OS were calculated from the date of stem cell infusion. The estimated 2-year PFS was 87.1%, and the estimated 2-year OS was 73.5%.

Patients who received BV-IGEV as first salvage fared better than those who received the regimen as second salvage. The PFS rates were 100% and 75%, respectively (P = .0078), and OS rates were 100% and 50%, respectively (P = .08).

Six patients relapsed after HSCT, and three died. Two patients died of progressive disease and one died of pulmonary infection.

These results suggest BV-IGEV can produce high response rates without compromising stem cell mobilization, but the combination should be investigated further, according to the researchers.

The researchers reported having no conflicts of interest.

[email protected]

SOURCE: Abuelgasim KA et al. Bone Marrow Transplant. 2019 Jan 30. doi: 10.1038/s41409-019-0454-z.

A retrospective study suggests a four-drug regimen can be effective salvage therapy for patients with relapsed or refractory classical Hodgkin lymphoma.

The regimen – brentuximab vedotin plus ifosfamide, gemcitabine, and vinorelbine (BV-IGEV) – produced responses in 27 of 28 patients studied, allowing them to undergo autologous hematopoietic stem cell transplant (HSCT).

After HSCT, the estimated 2-year progression-free survival (PFS) was 87.1% and the overall survival (OS) was 73.5%.

Though this study was limited by its small population and retrospective nature, the results “warrant further investigation,” according to Khadega A. Abuelgasim, MD, of King Abdullah International Medical Research Center in Riyadh, Saudi Arabia, and colleagues.

The researchers reported the results in a letter to Bone Marrow Transplantation.

The study included 28 patients with classical Hodgkin lymphoma, 15 of them male. The patients’ median age at HSCT was 25 years (range, 15-49 years). Twenty patients (71%) had constitutional symptoms at diagnosis, and eight (29%) had bulky disease.

Twenty-three patients (82%) received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline therapy, and four (14%) received ABVD followed by escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. One patient received a different frontline regimen.

The median time to relapse was 7.9 months (range, 1.9-133 months), and 12 patients (43%) were refractory to frontline treatment.

Half of patients (n = 14) received BV-IGEV as first salvage. The regimen was given as follows: ifosfamide at 2,000 mg/m² on days 1-4, gemcitabine at 800 mg/m² on days 1 and 4, vinorelbine at 20 mg/m² on day 1, prednisolone at 100 mg on days 1-4, and BV at a dose of 1.8 mg/kg on day 1 of each 3-week IGEV course.

All patients received at least two cycles of BV-IGEV and were assessed for response after one or two cycles. The median follow-up was 17 months (range, 0-65 months).

Twenty patients (71%) had a complete metabolic response to BV-IGEV, seven (25%) had a partial metabolic response, and one patient (4%) had stable disease. The patient with stable disease went on to receive another salvage regimen and achieved a partial response to that regimen.

The most common adverse events during BV-IGEV treatment were grade 3-4 neutropenia (n = 27; 96%) and thrombocytopenia (n = 25; 89%). Febrile neutropenia was also common (n = 16; 57%), as were mucositis (n = 6; 21%) and diarrhea (n = 6; 21%). Six patients had a reduction in BV dose because of an adverse event.

All patients underwent autologous HSCT. They received carmustine, etoposide, cytarabine, and melphalan as conditioning beforehand, and 18 patients (64%) received consolidative BV after transplant.

PFS and OS were calculated from the date of stem cell infusion. The estimated 2-year PFS was 87.1%, and the estimated 2-year OS was 73.5%.

Patients who received BV-IGEV as first salvage fared better than those who received the regimen as second salvage. The PFS rates were 100% and 75%, respectively (P = .0078), and OS rates were 100% and 50%, respectively (P = .08).

Six patients relapsed after HSCT, and three died. Two patients died of progressive disease and one died of pulmonary infection.

These results suggest BV-IGEV can produce high response rates without compromising stem cell mobilization, but the combination should be investigated further, according to the researchers.

The researchers reported having no conflicts of interest.

[email protected]

SOURCE: Abuelgasim KA et al. Bone Marrow Transplant. 2019 Jan 30. doi: 10.1038/s41409-019-0454-z.

A retrospective study suggests a four-drug regimen can be effective salvage therapy for patients with relapsed or refractory classical Hodgkin lymphoma.

The regimen – brentuximab vedotin plus ifosfamide, gemcitabine, and vinorelbine (BV-IGEV) – produced responses in 27 of 28 patients studied, allowing them to undergo autologous hematopoietic stem cell transplant (HSCT).

After HSCT, the estimated 2-year progression-free survival (PFS) was 87.1% and the overall survival (OS) was 73.5%.

Though this study was limited by its small population and retrospective nature, the results “warrant further investigation,” according to Khadega A. Abuelgasim, MD, of King Abdullah International Medical Research Center in Riyadh, Saudi Arabia, and colleagues.

The researchers reported the results in a letter to Bone Marrow Transplantation.

The study included 28 patients with classical Hodgkin lymphoma, 15 of them male. The patients’ median age at HSCT was 25 years (range, 15-49 years). Twenty patients (71%) had constitutional symptoms at diagnosis, and eight (29%) had bulky disease.

Twenty-three patients (82%) received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline therapy, and four (14%) received ABVD followed by escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. One patient received a different frontline regimen.

The median time to relapse was 7.9 months (range, 1.9-133 months), and 12 patients (43%) were refractory to frontline treatment.

Half of patients (n = 14) received BV-IGEV as first salvage. The regimen was given as follows: ifosfamide at 2,000 mg/m² on days 1-4, gemcitabine at 800 mg/m² on days 1 and 4, vinorelbine at 20 mg/m² on day 1, prednisolone at 100 mg on days 1-4, and BV at a dose of 1.8 mg/kg on day 1 of each 3-week IGEV course.

All patients received at least two cycles of BV-IGEV and were assessed for response after one or two cycles. The median follow-up was 17 months (range, 0-65 months).

Twenty patients (71%) had a complete metabolic response to BV-IGEV, seven (25%) had a partial metabolic response, and one patient (4%) had stable disease. The patient with stable disease went on to receive another salvage regimen and achieved a partial response to that regimen.

The most common adverse events during BV-IGEV treatment were grade 3-4 neutropenia (n = 27; 96%) and thrombocytopenia (n = 25; 89%). Febrile neutropenia was also common (n = 16; 57%), as were mucositis (n = 6; 21%) and diarrhea (n = 6; 21%). Six patients had a reduction in BV dose because of an adverse event.

All patients underwent autologous HSCT. They received carmustine, etoposide, cytarabine, and melphalan as conditioning beforehand, and 18 patients (64%) received consolidative BV after transplant.

PFS and OS were calculated from the date of stem cell infusion. The estimated 2-year PFS was 87.1%, and the estimated 2-year OS was 73.5%.

Patients who received BV-IGEV as first salvage fared better than those who received the regimen as second salvage. The PFS rates were 100% and 75%, respectively (P = .0078), and OS rates were 100% and 50%, respectively (P = .08).

Six patients relapsed after HSCT, and three died. Two patients died of progressive disease and one died of pulmonary infection.

These results suggest BV-IGEV can produce high response rates without compromising stem cell mobilization, but the combination should be investigated further, according to the researchers.

The researchers reported having no conflicts of interest.

[email protected]

SOURCE: Abuelgasim KA et al. Bone Marrow Transplant. 2019 Jan 30. doi: 10.1038/s41409-019-0454-z.

For patients with diffuse large B-cell lymphoma (DLBCL) who need allogeneic hematopoietic cell transplantation (allo-HCT), a haploidentical family member could be a viable donor, according to a retrospective study of 1,438 patients.

Nephron/Wikimedia Commons/CC BY-SA 3.0

When combined with nonmyeloablative/reduced intensity conditioning (NMC/RIC) and posttransplant cyclophosphamide (PTCy), patients treated with haploidentical HCT (haplo-HCT) had outcomes similar to those seen in patients with matched donors, reported Peter Dreger, MD, of the University of Heidelberg (Germany) and his colleagues.

“Using well-matched sibling donors (MSDs) or unrelated donors (MUDs), allo-HCT can result in sustained disease control in 30% to 45% of patients with DLBCL who have early disease recurrence after standard chemoimmunotherapy or have failed auto-HCT [autologous HCT],” the investigators wrote in Blood Advances. “However, the search for a well-matched unrelated donor could be time-consuming and unsuccessful in up to 50% of the patients in need.”

But the present findings suggest that haplo-HCT may one day improve these odds by providing a larger pool of potential donors.

The patients in the study were divided into four treatment groups: haplo-HCT (n = 132), MSD (n = 525), MUD with T-cell depletion (n = 403), and MUD without T-cell depletion (n = 378). For graft-versus-host disease (GVHD) prophylaxis, patients in the haplo-HCT group received PTCy, with or without a calcineurin inhibitor and mycophenolate mofetil, whereas all patients with matched donors received a calcineurin inhibitor. T-cell depletion was accomplished by in vivo antithymocyte globulin and alemtuzumab.

The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), progression/relapse, and nonrelapse mortality (NRM).

After a median follow-up of 4.1 years, all groups had similar outcomes, without statistical differences in multivariable analysis.

In the haplo-HCT group, the 3-year OS rate was 46%, the NRM rate was 22%, the PFS rate was 38%, and the relapse/progression rate was 41%.

Of note, patients receiving haplo-HCT did have a lower cumulative incidence of chronic GVHD, at 15% after 1 year and 18% after 2 years. These rates were significantly lower than the other groups’ 1- and 2-year GVHD rates, which were as follows: MSD, 41% and 48%; MUD with T-cell depletion, 23% and 27%; and MUD without T-cell depletion, 48% and 57%.

The investigators noted that these disparities may actually be caused by the use of bone marrow grafts in the haplo-HCT group instead of peripheral blood grafts, which were used in most of the patients in the other groups.

Overall, the findings were encouraging, but the investigators cautioned that “additional studies are needed before haploidentical donors can be considered as equivalent to well-matched related or unrelated donors in patients with DLBCL.”

The study was funded by the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation. CIBMTR is supported by grants from the U.S. government and the pharmaceutical industry. The authors reported having no competing financial interests.

SOURCE: Dreger P et al. Blood Adv. 2019 Feb 12;3(3):360-9.

For patients with diffuse large B-cell lymphoma (DLBCL) who need allogeneic hematopoietic cell transplantation (allo-HCT), a haploidentical family member could be a viable donor, according to a retrospective study of 1,438 patients.

Nephron/Wikimedia Commons/CC BY-SA 3.0

When combined with nonmyeloablative/reduced intensity conditioning (NMC/RIC) and posttransplant cyclophosphamide (PTCy), patients treated with haploidentical HCT (haplo-HCT) had outcomes similar to those seen in patients with matched donors, reported Peter Dreger, MD, of the University of Heidelberg (Germany) and his colleagues.

“Using well-matched sibling donors (MSDs) or unrelated donors (MUDs), allo-HCT can result in sustained disease control in 30% to 45% of patients with DLBCL who have early disease recurrence after standard chemoimmunotherapy or have failed auto-HCT [autologous HCT],” the investigators wrote in Blood Advances. “However, the search for a well-matched unrelated donor could be time-consuming and unsuccessful in up to 50% of the patients in need.”

But the present findings suggest that haplo-HCT may one day improve these odds by providing a larger pool of potential donors.

The patients in the study were divided into four treatment groups: haplo-HCT (n = 132), MSD (n = 525), MUD with T-cell depletion (n = 403), and MUD without T-cell depletion (n = 378). For graft-versus-host disease (GVHD) prophylaxis, patients in the haplo-HCT group received PTCy, with or without a calcineurin inhibitor and mycophenolate mofetil, whereas all patients with matched donors received a calcineurin inhibitor. T-cell depletion was accomplished by in vivo antithymocyte globulin and alemtuzumab.

The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), progression/relapse, and nonrelapse mortality (NRM).

After a median follow-up of 4.1 years, all groups had similar outcomes, without statistical differences in multivariable analysis.

In the haplo-HCT group, the 3-year OS rate was 46%, the NRM rate was 22%, the PFS rate was 38%, and the relapse/progression rate was 41%.

Of note, patients receiving haplo-HCT did have a lower cumulative incidence of chronic GVHD, at 15% after 1 year and 18% after 2 years. These rates were significantly lower than the other groups’ 1- and 2-year GVHD rates, which were as follows: MSD, 41% and 48%; MUD with T-cell depletion, 23% and 27%; and MUD without T-cell depletion, 48% and 57%.

The investigators noted that these disparities may actually be caused by the use of bone marrow grafts in the haplo-HCT group instead of peripheral blood grafts, which were used in most of the patients in the other groups.

Overall, the findings were encouraging, but the investigators cautioned that “additional studies are needed before haploidentical donors can be considered as equivalent to well-matched related or unrelated donors in patients with DLBCL.”

The study was funded by the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation. CIBMTR is supported by grants from the U.S. government and the pharmaceutical industry. The authors reported having no competing financial interests.

SOURCE: Dreger P et al. Blood Adv. 2019 Feb 12;3(3):360-9.

For patients with diffuse large B-cell lymphoma (DLBCL) who need allogeneic hematopoietic cell transplantation (allo-HCT), a haploidentical family member could be a viable donor, according to a retrospective study of 1,438 patients.

Nephron/Wikimedia Commons/CC BY-SA 3.0

When combined with nonmyeloablative/reduced intensity conditioning (NMC/RIC) and posttransplant cyclophosphamide (PTCy), patients treated with haploidentical HCT (haplo-HCT) had outcomes similar to those seen in patients with matched donors, reported Peter Dreger, MD, of the University of Heidelberg (Germany) and his colleagues.

“Using well-matched sibling donors (MSDs) or unrelated donors (MUDs), allo-HCT can result in sustained disease control in 30% to 45% of patients with DLBCL who have early disease recurrence after standard chemoimmunotherapy or have failed auto-HCT [autologous HCT],” the investigators wrote in Blood Advances. “However, the search for a well-matched unrelated donor could be time-consuming and unsuccessful in up to 50% of the patients in need.”

But the present findings suggest that haplo-HCT may one day improve these odds by providing a larger pool of potential donors.

The patients in the study were divided into four treatment groups: haplo-HCT (n = 132), MSD (n = 525), MUD with T-cell depletion (n = 403), and MUD without T-cell depletion (n = 378). For graft-versus-host disease (GVHD) prophylaxis, patients in the haplo-HCT group received PTCy, with or without a calcineurin inhibitor and mycophenolate mofetil, whereas all patients with matched donors received a calcineurin inhibitor. T-cell depletion was accomplished by in vivo antithymocyte globulin and alemtuzumab.

The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), progression/relapse, and nonrelapse mortality (NRM).

After a median follow-up of 4.1 years, all groups had similar outcomes, without statistical differences in multivariable analysis.

In the haplo-HCT group, the 3-year OS rate was 46%, the NRM rate was 22%, the PFS rate was 38%, and the relapse/progression rate was 41%.

Of note, patients receiving haplo-HCT did have a lower cumulative incidence of chronic GVHD, at 15% after 1 year and 18% after 2 years. These rates were significantly lower than the other groups’ 1- and 2-year GVHD rates, which were as follows: MSD, 41% and 48%; MUD with T-cell depletion, 23% and 27%; and MUD without T-cell depletion, 48% and 57%.

The investigators noted that these disparities may actually be caused by the use of bone marrow grafts in the haplo-HCT group instead of peripheral blood grafts, which were used in most of the patients in the other groups.

Overall, the findings were encouraging, but the investigators cautioned that “additional studies are needed before haploidentical donors can be considered as equivalent to well-matched related or unrelated donors in patients with DLBCL.”

The study was funded by the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation. CIBMTR is supported by grants from the U.S. government and the pharmaceutical industry. The authors reported having no competing financial interests.

SOURCE: Dreger P et al. Blood Adv. 2019 Feb 12;3(3):360-9.

The Food and Drug Administration (FDA) has granted priority review to a biologics license application (BLA) for polatuzumab vedotin, an anti-CD79b antibody drug conjugate.

With this BLA, Genentech is seeking approval for polatuzumab vedotin in combination with bendamustine and rituximab (BR) to treat patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency aims to take action on a priority review application within 6 months, rather than the standard 10 months.

The FDA is expected to make a decision on this BLA by Aug. 19, 2019.

The BLA is supported by a phase 1b/2 trial (NCT02257567) of patients with relapsed or refractory follicular lymphoma or DLBCL who received polatuzumab vedotin in combination with BR or obinutuzumab.

The trial’s phase 2 stage included 80 DLBCL patients who were randomized to receive BR or BR plus polatuzumab vedotin, according to Genentech.

The complete response rate was 40% in the polatuzumab vedotin arm and 18% in the BR arm. The median duration of response was 10.3 months and 4.1 months, respectively (hazard ratio [HR] = 0.44).

The median progression-free survival was 7.6 months in the polatuzumab vedotin arm and 2.0 months in the BR arm (HR = 0.34).

Among patients who were ineligible for a transplant, the median overall survival (an exploratory endpoint) was 12.4 months in the polatuzumab vedotin arm and 4.7 months in the BR arm (HR = 0.42).

Patients who received polatuzumab vedotin had higher rates of grade 3-4 cytopenias, compared with patients who received BR alone. Rates of infection and transfusion were similar between the arms.

[email protected]

The Food and Drug Administration (FDA) has granted priority review to a biologics license application (BLA) for polatuzumab vedotin, an anti-CD79b antibody drug conjugate.

With this BLA, Genentech is seeking approval for polatuzumab vedotin in combination with bendamustine and rituximab (BR) to treat patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency aims to take action on a priority review application within 6 months, rather than the standard 10 months.

The FDA is expected to make a decision on this BLA by Aug. 19, 2019.

The BLA is supported by a phase 1b/2 trial (NCT02257567) of patients with relapsed or refractory follicular lymphoma or DLBCL who received polatuzumab vedotin in combination with BR or obinutuzumab.

The trial’s phase 2 stage included 80 DLBCL patients who were randomized to receive BR or BR plus polatuzumab vedotin, according to Genentech.

The complete response rate was 40% in the polatuzumab vedotin arm and 18% in the BR arm. The median duration of response was 10.3 months and 4.1 months, respectively (hazard ratio [HR] = 0.44).

The median progression-free survival was 7.6 months in the polatuzumab vedotin arm and 2.0 months in the BR arm (HR = 0.34).

Among patients who were ineligible for a transplant, the median overall survival (an exploratory endpoint) was 12.4 months in the polatuzumab vedotin arm and 4.7 months in the BR arm (HR = 0.42).

Patients who received polatuzumab vedotin had higher rates of grade 3-4 cytopenias, compared with patients who received BR alone. Rates of infection and transfusion were similar between the arms.

[email protected]

The Food and Drug Administration (FDA) has granted priority review to a biologics license application (BLA) for polatuzumab vedotin, an anti-CD79b antibody drug conjugate.

With this BLA, Genentech is seeking approval for polatuzumab vedotin in combination with bendamustine and rituximab (BR) to treat patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency aims to take action on a priority review application within 6 months, rather than the standard 10 months.

The FDA is expected to make a decision on this BLA by Aug. 19, 2019.

The BLA is supported by a phase 1b/2 trial (NCT02257567) of patients with relapsed or refractory follicular lymphoma or DLBCL who received polatuzumab vedotin in combination with BR or obinutuzumab.

The trial’s phase 2 stage included 80 DLBCL patients who were randomized to receive BR or BR plus polatuzumab vedotin, according to Genentech.

The complete response rate was 40% in the polatuzumab vedotin arm and 18% in the BR arm. The median duration of response was 10.3 months and 4.1 months, respectively (hazard ratio [HR] = 0.44).

The median progression-free survival was 7.6 months in the polatuzumab vedotin arm and 2.0 months in the BR arm (HR = 0.34).

Among patients who were ineligible for a transplant, the median overall survival (an exploratory endpoint) was 12.4 months in the polatuzumab vedotin arm and 4.7 months in the BR arm (HR = 0.42).

Patients who received polatuzumab vedotin had higher rates of grade 3-4 cytopenias, compared with patients who received BR alone. Rates of infection and transfusion were similar between the arms.

[email protected]

Researchers say they have characterized a subtype of diffuse large B-cell lymphoma (DLBCL) with distinct molecular features and poor prognosis.

Patients with this subtype, dubbed “molecular high-grade” (MHG) DLBCL, were more likely to have germinal center B-cell-like (GCB) DLBCL, MYC rearrangements, and double-hit lymphoma.

When compared to other DLBCL patients, those with MHG DLBCL had inferior progression-free and overall survival.

Chulin Sha, PhD, of the University of Leeds (England), and colleagues reported these findings in the Journal of Clinical Oncology. The findings were published alongside a related editorial and a similar study from another group.

Dr. Sha and colleagues began their study by applying a previously developed gene expression classifier (Genome Med. 2015 Jul 1;7[1]:64) to 928 DLBCL patients enrolled in the REMoDL-B trial. REMoDL-B was designed to compare rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to R-CHOP plus bortezomib (Hematol Oncol. 2017;35:130-1).

Dr. Sha and colleagues looked for somatic mutations in 400 REMoDL-B patient samples that were sequenced for a 70-gene panel.

The team also tested 360 samples for MYC, BCL2, and BCL6 chromosomal rearrangements using fluorescent in situ hybridization, and they tested 355 samples for MYC and BCL2 protein expression with immunohistochemistry.

Characteristics of MHG DLBCL

The researchers identified 83 REMoDL-B patients as having MHG DLBCL (9%). Most of the MHG patients had GCB DLBCL (90%), 48.6% had MYC rearrangements, and 36.1% had double-hit lymphoma.

Patients with MHG DLBCL had higher International Prognostic Index scores (P = .004), greater tumor bulk (P = .007), higher disease stage (P = .06), and higher lactate dehydrogenase levels (P less than .001) than patients with non-MHG DLBCL.

Although most MHG patients had GCB DLBCL, the researchers found key differences between patients with MHG DLBCL and non-MHG GCB DLBCL. MHG patients were significantly more likely than patients with non-MHG GCB DLBCL to have mutations in KMT2D, BCL2, MYC, and DDX3X. Additionally, some genes frequently mutated in GCB DLBCL — such as B2M, SGK1, and NFKBIA — were rare in MHG DLBCL.

Dr. Sha and colleagues also compared the MHG patients to 70 patients with Burkitt lymphoma (BL) who had been analyzed in a previous study (Genome Med. 2015 Jul 1;7[1]:64).

The researchers found that BL has more upregulated genes than GCB (2,483 genes) and MHG DLBCL (1,784 genes), and MHG DLBCL has more upregulated genes than GCB DLBCL (382 genes). The team observed a similar pattern with downregulated genes and said this suggests “MHG is an intermediate group but closer to GCB than to BL.”

• 37% for MHG patients
• 78% for patients with GCB DLBCL
• 64% for patients with activated B-cell like (ABC) DLBCL
• 65% for patients with unclassified DLBCL.

Among patients who received bortezomib plus R-CHOP, there was a trend toward improved PFS for patients with MHG DLBCL (58%; P = .08).

Validation cohort

Dr. Sha and colleagues validated their initial findings using RNA sequencing data from another group of DLBCL patients (Cell. 2017 Oct 5;171[2]:481-94.e15). This data set included 624 patients who received rituximab-based therapy.

Seventy-two patients in this group had MHG DLBCL (11.5%), and most MHG patients had GCB DLBCL (82%).

The researchers said the MHG group in this cohort “showed similar associations with clinical variables” and a “similar mutation spectrum” as the MHG group in the REMoDL-B cohort. Additionally, MHG patients in the validation cohort had inferior overall survival (P less than .001) compared to patients with non-MHG GCB DLBCL.

Dr. Sha and colleagues said the poor prognosis in MHG patients in both cohorts suggests a need for different treatment approaches in this group.

In the related editorial, Wing C. Chan, MD, of City of Hope Medical Center in Duarte, Calif., echoed that sentiment and said it will be important to include patients with high-risk DLBCL in clinical trials.

“Their tumors should be comprehensively characterize[d] for correlative analysis to determine the molecular lesions that underlie their biology and response to treatment,” Dr. Chan wrote.

Dr. Chan disclosed a patent for a diagnostic algorithm on GCB/ABC-type DLBCL and a patent on a diagnostic algorithm for peripheral T-cell lymphoma.

Dr. Sha and colleagues disclosed relationships with a range of pharmaceutical companies. The team’s research was supported by a grant from Bloodwise.

The REMoDL-B trial was endorsed by Cancer Research UK and was funded by Janssen-Cillag.

[email protected]

SOURCES: Sha C et al. J Clin Oncol. 2019 Jan 20;37(3):202-12. doi: 10.1200/JCO.18.01314; Chan WC. J Clin Oncol. 2019 Jan 20;37(3):175-7. doi: 10.1200/JCO.18.01910; Ennishi D et al. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583

Researchers say they have characterized a subtype of diffuse large B-cell lymphoma (DLBCL) with distinct molecular features and poor prognosis.

Patients with this subtype, dubbed “molecular high-grade” (MHG) DLBCL, were more likely to have germinal center B-cell-like (GCB) DLBCL, MYC rearrangements, and double-hit lymphoma.

When compared to other DLBCL patients, those with MHG DLBCL had inferior progression-free and overall survival.

Chulin Sha, PhD, of the University of Leeds (England), and colleagues reported these findings in the Journal of Clinical Oncology. The findings were published alongside a related editorial and a similar study from another group.

Dr. Sha and colleagues began their study by applying a previously developed gene expression classifier (Genome Med. 2015 Jul 1;7[1]:64) to 928 DLBCL patients enrolled in the REMoDL-B trial. REMoDL-B was designed to compare rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to R-CHOP plus bortezomib (Hematol Oncol. 2017;35:130-1).

Dr. Sha and colleagues looked for somatic mutations in 400 REMoDL-B patient samples that were sequenced for a 70-gene panel.

The team also tested 360 samples for MYC, BCL2, and BCL6 chromosomal rearrangements using fluorescent in situ hybridization, and they tested 355 samples for MYC and BCL2 protein expression with immunohistochemistry.

Characteristics of MHG DLBCL

The researchers identified 83 REMoDL-B patients as having MHG DLBCL (9%). Most of the MHG patients had GCB DLBCL (90%), 48.6% had MYC rearrangements, and 36.1% had double-hit lymphoma.

Patients with MHG DLBCL had higher International Prognostic Index scores (P = .004), greater tumor bulk (P = .007), higher disease stage (P = .06), and higher lactate dehydrogenase levels (P less than .001) than patients with non-MHG DLBCL.

Although most MHG patients had GCB DLBCL, the researchers found key differences between patients with MHG DLBCL and non-MHG GCB DLBCL. MHG patients were significantly more likely than patients with non-MHG GCB DLBCL to have mutations in KMT2D, BCL2, MYC, and DDX3X. Additionally, some genes frequently mutated in GCB DLBCL — such as B2M, SGK1, and NFKBIA — were rare in MHG DLBCL.

Dr. Sha and colleagues also compared the MHG patients to 70 patients with Burkitt lymphoma (BL) who had been analyzed in a previous study (Genome Med. 2015 Jul 1;7[1]:64).

The researchers found that BL has more upregulated genes than GCB (2,483 genes) and MHG DLBCL (1,784 genes), and MHG DLBCL has more upregulated genes than GCB DLBCL (382 genes). The team observed a similar pattern with downregulated genes and said this suggests “MHG is an intermediate group but closer to GCB than to BL.”

• 37% for MHG patients
• 78% for patients with GCB DLBCL
• 64% for patients with activated B-cell like (ABC) DLBCL
• 65% for patients with unclassified DLBCL.

Among patients who received bortezomib plus R-CHOP, there was a trend toward improved PFS for patients with MHG DLBCL (58%; P = .08).

Validation cohort

Dr. Sha and colleagues validated their initial findings using RNA sequencing data from another group of DLBCL patients (Cell. 2017 Oct 5;171[2]:481-94.e15). This data set included 624 patients who received rituximab-based therapy.

Seventy-two patients in this group had MHG DLBCL (11.5%), and most MHG patients had GCB DLBCL (82%).

The researchers said the MHG group in this cohort “showed similar associations with clinical variables” and a “similar mutation spectrum” as the MHG group in the REMoDL-B cohort. Additionally, MHG patients in the validation cohort had inferior overall survival (P less than .001) compared to patients with non-MHG GCB DLBCL.

Dr. Sha and colleagues said the poor prognosis in MHG patients in both cohorts suggests a need for different treatment approaches in this group.

In the related editorial, Wing C. Chan, MD, of City of Hope Medical Center in Duarte, Calif., echoed that sentiment and said it will be important to include patients with high-risk DLBCL in clinical trials.

“Their tumors should be comprehensively characterize[d] for correlative analysis to determine the molecular lesions that underlie their biology and response to treatment,” Dr. Chan wrote.

Dr. Chan disclosed a patent for a diagnostic algorithm on GCB/ABC-type DLBCL and a patent on a diagnostic algorithm for peripheral T-cell lymphoma.

Dr. Sha and colleagues disclosed relationships with a range of pharmaceutical companies. The team’s research was supported by a grant from Bloodwise.

The REMoDL-B trial was endorsed by Cancer Research UK and was funded by Janssen-Cillag.

[email protected]

SOURCES: Sha C et al. J Clin Oncol. 2019 Jan 20;37(3):202-12. doi: 10.1200/JCO.18.01314; Chan WC. J Clin Oncol. 2019 Jan 20;37(3):175-7. doi: 10.1200/JCO.18.01910; Ennishi D et al. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583

Researchers say they have characterized a subtype of diffuse large B-cell lymphoma (DLBCL) with distinct molecular features and poor prognosis.

Patients with this subtype, dubbed “molecular high-grade” (MHG) DLBCL, were more likely to have germinal center B-cell-like (GCB) DLBCL, MYC rearrangements, and double-hit lymphoma.

When compared to other DLBCL patients, those with MHG DLBCL had inferior progression-free and overall survival.

Chulin Sha, PhD, of the University of Leeds (England), and colleagues reported these findings in the Journal of Clinical Oncology. The findings were published alongside a related editorial and a similar study from another group.

Dr. Sha and colleagues began their study by applying a previously developed gene expression classifier (Genome Med. 2015 Jul 1;7[1]:64) to 928 DLBCL patients enrolled in the REMoDL-B trial. REMoDL-B was designed to compare rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to R-CHOP plus bortezomib (Hematol Oncol. 2017;35:130-1).

Dr. Sha and colleagues looked for somatic mutations in 400 REMoDL-B patient samples that were sequenced for a 70-gene panel.

The team also tested 360 samples for MYC, BCL2, and BCL6 chromosomal rearrangements using fluorescent in situ hybridization, and they tested 355 samples for MYC and BCL2 protein expression with immunohistochemistry.

Characteristics of MHG DLBCL

The researchers identified 83 REMoDL-B patients as having MHG DLBCL (9%). Most of the MHG patients had GCB DLBCL (90%), 48.6% had MYC rearrangements, and 36.1% had double-hit lymphoma.

Patients with MHG DLBCL had higher International Prognostic Index scores (P = .004), greater tumor bulk (P = .007), higher disease stage (P = .06), and higher lactate dehydrogenase levels (P less than .001) than patients with non-MHG DLBCL.

Although most MHG patients had GCB DLBCL, the researchers found key differences between patients with MHG DLBCL and non-MHG GCB DLBCL. MHG patients were significantly more likely than patients with non-MHG GCB DLBCL to have mutations in KMT2D, BCL2, MYC, and DDX3X. Additionally, some genes frequently mutated in GCB DLBCL — such as B2M, SGK1, and NFKBIA — were rare in MHG DLBCL.

Dr. Sha and colleagues also compared the MHG patients to 70 patients with Burkitt lymphoma (BL) who had been analyzed in a previous study (Genome Med. 2015 Jul 1;7[1]:64).

The researchers found that BL has more upregulated genes than GCB (2,483 genes) and MHG DLBCL (1,784 genes), and MHG DLBCL has more upregulated genes than GCB DLBCL (382 genes). The team observed a similar pattern with downregulated genes and said this suggests “MHG is an intermediate group but closer to GCB than to BL.”

• 37% for MHG patients
• 78% for patients with GCB DLBCL
• 64% for patients with activated B-cell like (ABC) DLBCL
• 65% for patients with unclassified DLBCL.

Among patients who received bortezomib plus R-CHOP, there was a trend toward improved PFS for patients with MHG DLBCL (58%; P = .08).

Validation cohort

Dr. Sha and colleagues validated their initial findings using RNA sequencing data from another group of DLBCL patients (Cell. 2017 Oct 5;171[2]:481-94.e15). This data set included 624 patients who received rituximab-based therapy.

Seventy-two patients in this group had MHG DLBCL (11.5%), and most MHG patients had GCB DLBCL (82%).

The researchers said the MHG group in this cohort “showed similar associations with clinical variables” and a “similar mutation spectrum” as the MHG group in the REMoDL-B cohort. Additionally, MHG patients in the validation cohort had inferior overall survival (P less than .001) compared to patients with non-MHG GCB DLBCL.

Dr. Sha and colleagues said the poor prognosis in MHG patients in both cohorts suggests a need for different treatment approaches in this group.

In the related editorial, Wing C. Chan, MD, of City of Hope Medical Center in Duarte, Calif., echoed that sentiment and said it will be important to include patients with high-risk DLBCL in clinical trials.

“Their tumors should be comprehensively characterize[d] for correlative analysis to determine the molecular lesions that underlie their biology and response to treatment,” Dr. Chan wrote.

Dr. Chan disclosed a patent for a diagnostic algorithm on GCB/ABC-type DLBCL and a patent on a diagnostic algorithm for peripheral T-cell lymphoma.

Dr. Sha and colleagues disclosed relationships with a range of pharmaceutical companies. The team’s research was supported by a grant from Bloodwise.

The REMoDL-B trial was endorsed by Cancer Research UK and was funded by Janssen-Cillag.

[email protected]

SOURCES: Sha C et al. J Clin Oncol. 2019 Jan 20;37(3):202-12. doi: 10.1200/JCO.18.01314; Chan WC. J Clin Oncol. 2019 Jan 20;37(3):175-7. doi: 10.1200/JCO.18.01910; Ennishi D et al. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583

One chimeric antigen receptor (CAR) T-cell therapy may appear better than another, but confounding factors make it difficult to compare these therapies effectively, according to a review published in the Journal of Clinical Oncology.

Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, reviewed results from three trials of CAR T-cell therapies in patients with B-cell non-Hodgkin lymphoma (B-NHL).

She noted that cross-trial comparisons are always limited, but such comparisons of CAR T-cell therapies are hindered by several confounding factors.

Dr. Jacobson said differences in manufacturing procedures and turnaround time, differences in patient eligibility and management, and the complexity of CAR T-cell therapies make it difficult to compare results from three CAR-T trials in B-NHL:

• The ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel, Yescarta)
• The JULIET trial (NCT02445248) of tisagenlecleucel (t-cel, Kymriah)
• The TRANSCEND-NHL-001 trial (NCT02631044) of lisocabtagene maraleucel (liso-cel, JCAR017).

Looking at response rates alone, axi-cel appears the most promising. The overall response rate (ORR) was 82% with axi-cel, 75% with liso-cel, and 52% with t-cel.

When considering cytokine release syndrome (CRS), liso-cel appears the safest. The rate of CRS was 93% with axi-cel (13% grade 3 or higher), 58% with t-cel (22% grade 3 or higher), and 39% with liso-cel (1% grade 3 or higher).

However, as Dr. Jacobson pointed out, it’s impossible to know if these differences in efficacy and toxicity are “statistically meaningful.”

[email protected]

SOURCE: Jacobson CA. J Clin Oncol. 2019 Feb 1;37(4):328-35. doi: 10.1200/JCO.18.01457

One chimeric antigen receptor (CAR) T-cell therapy may appear better than another, but confounding factors make it difficult to compare these therapies effectively, according to a review published in the Journal of Clinical Oncology.

Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, reviewed results from three trials of CAR T-cell therapies in patients with B-cell non-Hodgkin lymphoma (B-NHL).

She noted that cross-trial comparisons are always limited, but such comparisons of CAR T-cell therapies are hindered by several confounding factors.

Dr. Jacobson said differences in manufacturing procedures and turnaround time, differences in patient eligibility and management, and the complexity of CAR T-cell therapies make it difficult to compare results from three CAR-T trials in B-NHL:

• The ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel, Yescarta)
• The JULIET trial (NCT02445248) of tisagenlecleucel (t-cel, Kymriah)
• The TRANSCEND-NHL-001 trial (NCT02631044) of lisocabtagene maraleucel (liso-cel, JCAR017).

Looking at response rates alone, axi-cel appears the most promising. The overall response rate (ORR) was 82% with axi-cel, 75% with liso-cel, and 52% with t-cel.

When considering cytokine release syndrome (CRS), liso-cel appears the safest. The rate of CRS was 93% with axi-cel (13% grade 3 or higher), 58% with t-cel (22% grade 3 or higher), and 39% with liso-cel (1% grade 3 or higher).

However, as Dr. Jacobson pointed out, it’s impossible to know if these differences in efficacy and toxicity are “statistically meaningful.”

[email protected]

SOURCE: Jacobson CA. J Clin Oncol. 2019 Feb 1;37(4):328-35. doi: 10.1200/JCO.18.01457

One chimeric antigen receptor (CAR) T-cell therapy may appear better than another, but confounding factors make it difficult to compare these therapies effectively, according to a review published in the Journal of Clinical Oncology.

Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, reviewed results from three trials of CAR T-cell therapies in patients with B-cell non-Hodgkin lymphoma (B-NHL).

She noted that cross-trial comparisons are always limited, but such comparisons of CAR T-cell therapies are hindered by several confounding factors.

Dr. Jacobson said differences in manufacturing procedures and turnaround time, differences in patient eligibility and management, and the complexity of CAR T-cell therapies make it difficult to compare results from three CAR-T trials in B-NHL:

• The ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel, Yescarta)
• The JULIET trial (NCT02445248) of tisagenlecleucel (t-cel, Kymriah)
• The TRANSCEND-NHL-001 trial (NCT02631044) of lisocabtagene maraleucel (liso-cel, JCAR017).

Looking at response rates alone, axi-cel appears the most promising. The overall response rate (ORR) was 82% with axi-cel, 75% with liso-cel, and 52% with t-cel.

When considering cytokine release syndrome (CRS), liso-cel appears the safest. The rate of CRS was 93% with axi-cel (13% grade 3 or higher), 58% with t-cel (22% grade 3 or higher), and 39% with liso-cel (1% grade 3 or higher).

However, as Dr. Jacobson pointed out, it’s impossible to know if these differences in efficacy and toxicity are “statistically meaningful.”

[email protected]

SOURCE: Jacobson CA. J Clin Oncol. 2019 Feb 1;37(4):328-35. doi: 10.1200/JCO.18.01457

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]