Mantle Cell Lymphoma

LUGANO, Switzerland – In younger patients with previously untreated mantle cell lymphoma, the chemotherapy-free combination of ibrutinib and rituximab followed by a short course of chemotherapy was associated with an “unprecedented” 3-year progression-free survival rate, investigators in the phase 2 WINDOW-1 trial reported.

Neil Osterweil/MDedge News

Among 50 patients aged 65 years and younger who received ibrutinib and rituximab until they achieved a complete or partial response, followed by four cycles of chemotherapy with rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) and rituximab plus methotrexate, the 3-year progression-free survival (PFS) rate was 88%, said Michael Wang, MD, from the University of Texas MD Anderson Cancer Center in Houston.

Additionally, for patients with the low-risk features, the 3-year PFS rate was 90%.

“Chemo-free ibrutinib-rituximab induced unprecedented – unprecedented – efficacy before chemo consolidation,” he said at the International Conference on Malignant Lymphoma.

Dr. Wang presented data from an interim analysis of the investigator-initiated single-center trial. Fifty patients aged 65 years or younger with untreated mantle cell lymphoma (MCL), good performance status, and good organ function were enrolled.

The patients were treated with ibrutinib and rituximab for two cycles and then evaluated for response with PET-CT scan, bone marrow biopsy, and for some patients, esophagogastroduodenoscopy (EGD) and colonoscopy with random biopsies.

In the induction phase, patients received ibrutinib daily on days 1-28 and rituximab intravenously over 6-8 hours on days 1, 8, 15, and 22 of cycle 1, and then over 4 hours on day 1 of cycles 3-12. The treatment was repeated every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity, or until patients achieved a complete response.

In the consolidation phase, patients received rituximab IV over 6 hours on day 1; oral or IV dexamethasone on days 1-4; cyclophosphamide IV over 3 hours twice daily on days 2-4; doxorubicin IV over 15-30 minutes on day 5; and vincristine IV over 15-30 minutes on day 5 of cycles one, three, five, and seven. Patients also received rituximab IV over 6 hours on day 1; methotrexate IV over 24 hours on day 2; and cytarabine IV over 2 hours twice daily on days 3 and 4 of cycles two, four, six, and eight. Treatments were repeated every 28 days for up to eight cycles in the absence of disease progression or unacceptable toxicity.

Patients who had a complete response (CR) after two cycles of induction and those who had disease progression on induction went on to consolidation. Patients with partial responses (PR) to induction continued on ibrutinib/rituximab until either the loss of a PR or best response for up to 12 cycles, with those who achieved a CR then moving on to consolidation.

Patients who had a CR after induction received four cycles of R-hyperCVAD, no subsequent stem cell transplant, and no maintenance therapy. Patients who had a PR after induction received two cycles of R-hyperCVAD, were reassessed, and then continued on R-hyperCVAD until CR or for up to eight total cycles.

Patients with either stable disease or progression during R-hyperCVAD were taken off the study.

Of the 50 patients enrolled, all 50 were evaluable for part A (induction), and 48 were evaluable after induction and consolidation (two patients withdrew for personal reasons).

After a median follow-up of 36 months, the overall response rate (ORR) following induction was 100%, consisting of 46 CRs (92%) and four PRs (8%).

In an intention-to-treat analysis (including the two patients who withdrew), the ORR was 96%, consisting of CRs in 47 patients (94%) and a PR in 1 patient (2%).

Neither the median PFS nor median overall survival had been reached at the time of data cutoff, and no patients have died.

Of the 50 enrolled patients, four experienced disease progression after 17, 24, 34, and 35 months of treatment. The patients with disease progression included one with Ki-67 of less than 30%, and three with KI-67 of 30% or greater.

Grade 3-4 toxicities during induction including myelosuppression in 4%; fatigue, myalgia, and rashes in 8% each; and oral mucositis in 4%.

Dr. Wang said that future studies on minimal residual disease and clonal evolution are ongoing, and that data on more patients will be presented at the next annual meeting of the American Society of Hematology, scheduled for December 2019.

He also noted that the WINDOW-2 trial, in which ibrutinib and rituximab are followed by veneotclax and hyper-CVAD chemotherapy in patients with newly diagnosed MCL, is open and rapidly enrolling patients.

The study is supported by the National Cancer Institute. Dr. Wang reported financial relationships with Janssen, Pharmacyclics, and other companies.

SOURCE: Wang M et al. ICML-15, Abstract 12.

LUGANO, Switzerland – In younger patients with previously untreated mantle cell lymphoma, the chemotherapy-free combination of ibrutinib and rituximab followed by a short course of chemotherapy was associated with an “unprecedented” 3-year progression-free survival rate, investigators in the phase 2 WINDOW-1 trial reported.

Neil Osterweil/MDedge News

Among 50 patients aged 65 years and younger who received ibrutinib and rituximab until they achieved a complete or partial response, followed by four cycles of chemotherapy with rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) and rituximab plus methotrexate, the 3-year progression-free survival (PFS) rate was 88%, said Michael Wang, MD, from the University of Texas MD Anderson Cancer Center in Houston.

Additionally, for patients with the low-risk features, the 3-year PFS rate was 90%.

“Chemo-free ibrutinib-rituximab induced unprecedented – unprecedented – efficacy before chemo consolidation,” he said at the International Conference on Malignant Lymphoma.

Dr. Wang presented data from an interim analysis of the investigator-initiated single-center trial. Fifty patients aged 65 years or younger with untreated mantle cell lymphoma (MCL), good performance status, and good organ function were enrolled.

The patients were treated with ibrutinib and rituximab for two cycles and then evaluated for response with PET-CT scan, bone marrow biopsy, and for some patients, esophagogastroduodenoscopy (EGD) and colonoscopy with random biopsies.

In the induction phase, patients received ibrutinib daily on days 1-28 and rituximab intravenously over 6-8 hours on days 1, 8, 15, and 22 of cycle 1, and then over 4 hours on day 1 of cycles 3-12. The treatment was repeated every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity, or until patients achieved a complete response.

In the consolidation phase, patients received rituximab IV over 6 hours on day 1; oral or IV dexamethasone on days 1-4; cyclophosphamide IV over 3 hours twice daily on days 2-4; doxorubicin IV over 15-30 minutes on day 5; and vincristine IV over 15-30 minutes on day 5 of cycles one, three, five, and seven. Patients also received rituximab IV over 6 hours on day 1; methotrexate IV over 24 hours on day 2; and cytarabine IV over 2 hours twice daily on days 3 and 4 of cycles two, four, six, and eight. Treatments were repeated every 28 days for up to eight cycles in the absence of disease progression or unacceptable toxicity.

Patients who had a complete response (CR) after two cycles of induction and those who had disease progression on induction went on to consolidation. Patients with partial responses (PR) to induction continued on ibrutinib/rituximab until either the loss of a PR or best response for up to 12 cycles, with those who achieved a CR then moving on to consolidation.

Patients who had a CR after induction received four cycles of R-hyperCVAD, no subsequent stem cell transplant, and no maintenance therapy. Patients who had a PR after induction received two cycles of R-hyperCVAD, were reassessed, and then continued on R-hyperCVAD until CR or for up to eight total cycles.

Patients with either stable disease or progression during R-hyperCVAD were taken off the study.

Of the 50 patients enrolled, all 50 were evaluable for part A (induction), and 48 were evaluable after induction and consolidation (two patients withdrew for personal reasons).

After a median follow-up of 36 months, the overall response rate (ORR) following induction was 100%, consisting of 46 CRs (92%) and four PRs (8%).

In an intention-to-treat analysis (including the two patients who withdrew), the ORR was 96%, consisting of CRs in 47 patients (94%) and a PR in 1 patient (2%).

Neither the median PFS nor median overall survival had been reached at the time of data cutoff, and no patients have died.

Of the 50 enrolled patients, four experienced disease progression after 17, 24, 34, and 35 months of treatment. The patients with disease progression included one with Ki-67 of less than 30%, and three with KI-67 of 30% or greater.

Grade 3-4 toxicities during induction including myelosuppression in 4%; fatigue, myalgia, and rashes in 8% each; and oral mucositis in 4%.

Dr. Wang said that future studies on minimal residual disease and clonal evolution are ongoing, and that data on more patients will be presented at the next annual meeting of the American Society of Hematology, scheduled for December 2019.

He also noted that the WINDOW-2 trial, in which ibrutinib and rituximab are followed by veneotclax and hyper-CVAD chemotherapy in patients with newly diagnosed MCL, is open and rapidly enrolling patients.

The study is supported by the National Cancer Institute. Dr. Wang reported financial relationships with Janssen, Pharmacyclics, and other companies.

SOURCE: Wang M et al. ICML-15, Abstract 12.

LUGANO, Switzerland – In younger patients with previously untreated mantle cell lymphoma, the chemotherapy-free combination of ibrutinib and rituximab followed by a short course of chemotherapy was associated with an “unprecedented” 3-year progression-free survival rate, investigators in the phase 2 WINDOW-1 trial reported.

Neil Osterweil/MDedge News

Among 50 patients aged 65 years and younger who received ibrutinib and rituximab until they achieved a complete or partial response, followed by four cycles of chemotherapy with rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) and rituximab plus methotrexate, the 3-year progression-free survival (PFS) rate was 88%, said Michael Wang, MD, from the University of Texas MD Anderson Cancer Center in Houston.

Additionally, for patients with the low-risk features, the 3-year PFS rate was 90%.

“Chemo-free ibrutinib-rituximab induced unprecedented – unprecedented – efficacy before chemo consolidation,” he said at the International Conference on Malignant Lymphoma.

Dr. Wang presented data from an interim analysis of the investigator-initiated single-center trial. Fifty patients aged 65 years or younger with untreated mantle cell lymphoma (MCL), good performance status, and good organ function were enrolled.

The patients were treated with ibrutinib and rituximab for two cycles and then evaluated for response with PET-CT scan, bone marrow biopsy, and for some patients, esophagogastroduodenoscopy (EGD) and colonoscopy with random biopsies.

In the induction phase, patients received ibrutinib daily on days 1-28 and rituximab intravenously over 6-8 hours on days 1, 8, 15, and 22 of cycle 1, and then over 4 hours on day 1 of cycles 3-12. The treatment was repeated every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity, or until patients achieved a complete response.

In the consolidation phase, patients received rituximab IV over 6 hours on day 1; oral or IV dexamethasone on days 1-4; cyclophosphamide IV over 3 hours twice daily on days 2-4; doxorubicin IV over 15-30 minutes on day 5; and vincristine IV over 15-30 minutes on day 5 of cycles one, three, five, and seven. Patients also received rituximab IV over 6 hours on day 1; methotrexate IV over 24 hours on day 2; and cytarabine IV over 2 hours twice daily on days 3 and 4 of cycles two, four, six, and eight. Treatments were repeated every 28 days for up to eight cycles in the absence of disease progression or unacceptable toxicity.

Patients who had a complete response (CR) after two cycles of induction and those who had disease progression on induction went on to consolidation. Patients with partial responses (PR) to induction continued on ibrutinib/rituximab until either the loss of a PR or best response for up to 12 cycles, with those who achieved a CR then moving on to consolidation.

Patients who had a CR after induction received four cycles of R-hyperCVAD, no subsequent stem cell transplant, and no maintenance therapy. Patients who had a PR after induction received two cycles of R-hyperCVAD, were reassessed, and then continued on R-hyperCVAD until CR or for up to eight total cycles.

Patients with either stable disease or progression during R-hyperCVAD were taken off the study.

Of the 50 patients enrolled, all 50 were evaluable for part A (induction), and 48 were evaluable after induction and consolidation (two patients withdrew for personal reasons).

After a median follow-up of 36 months, the overall response rate (ORR) following induction was 100%, consisting of 46 CRs (92%) and four PRs (8%).

In an intention-to-treat analysis (including the two patients who withdrew), the ORR was 96%, consisting of CRs in 47 patients (94%) and a PR in 1 patient (2%).

Neither the median PFS nor median overall survival had been reached at the time of data cutoff, and no patients have died.

Of the 50 enrolled patients, four experienced disease progression after 17, 24, 34, and 35 months of treatment. The patients with disease progression included one with Ki-67 of less than 30%, and three with KI-67 of 30% or greater.

Grade 3-4 toxicities during induction including myelosuppression in 4%; fatigue, myalgia, and rashes in 8% each; and oral mucositis in 4%.

Dr. Wang said that future studies on minimal residual disease and clonal evolution are ongoing, and that data on more patients will be presented at the next annual meeting of the American Society of Hematology, scheduled for December 2019.

He also noted that the WINDOW-2 trial, in which ibrutinib and rituximab are followed by veneotclax and hyper-CVAD chemotherapy in patients with newly diagnosed MCL, is open and rapidly enrolling patients.

The study is supported by the National Cancer Institute. Dr. Wang reported financial relationships with Janssen, Pharmacyclics, and other companies.

SOURCE: Wang M et al. ICML-15, Abstract 12.

LUGANO, SWITZERLAND – The chemotherapy-free combination of ibrutinib (Imbruvica) and rituximab is highly effective as frontline therapy for older, transplant-ineligible patients with nonblastoid mantle cell lymphoma, according to investigators.

Neil Osterweil/MDedge News

In a phase 2 study of patients with a median age of 71 years, 38 of 41 patients (93%) had an objective response, and the regimen was both safe and easy to administer, reported Preetesh Jain, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

“The adverse event profile was generally favorable, with specific monitoring recommended for patients with cardiovascular comorbidities and a history of atrial fibrillation,” he said at the International Conference on Malignant Lymphoma.

The investigators enrolled 48 patients aged 65 years and older with previously untreated mantle cell lymphoma (MCL), of whom 41 were evaluable for the primary endpoints of overall response rate (ORR) and safety. The patients had good performance status and normal organ function, with the largest tumor size less than 10 cm. Patients with atrial fibrillation could participate, if the fibrillation was controlled. Patients with Ki-67 protein levels of 50% or greater and blastoid/pleomorphic histology were excluded.

Patients were treated with ibrutinib 560 mg orally daily for each 28-day cycle, with therapy continued until disease progression, or until therapy was stopped for any other reason. Patients also received intravenous rituximab 375 mg/m² on days 1, 8, 15 and 22, plus or minus one day for cycle 1, on day 1 of cycles 3-8, and on day 1 of every other cycle for up to 2 years.

Of the 41 patients evaluable for response, 26 (64%) had a complete response (CR) and 12 (29%) had a partial response. Three additional patients had stable disease, for an objective response rate of 93%.

Of 34 patients with PET scans, all had negative scans. Of 37 patients evaluable for minimal residual disease (MRD) by flow cytometry, 21 (58%) were MRD negative.

Patients with low or intermediate Mantle Cell Lymphoma International Prognostic Index (MIPI) scores had a higher ORR (100% vs. 89% for patients with high MIPI scores), and patients with low Ki-67 levels had a higher response rate than that of patients with KI-67 of 30% or greater (80% vs. 87%).

Neither median 3-year progression-free survival nor median 3-year overall survival have been reached, with respective 3-year rates of 87% and 95%.

Four patients experienced disease progression at 4, 10, 13 and 33 months of treatment. Three of these patients had disease that had transformed to blastoid/pleomorphic variant, two had Ki-67 of 30% or greater, one had mutations in TP53, and one had FAT1 and SF3B1 mutations.


Two patients died after ibrutinib therapy, one who had discontinued therapy because of bleeding, and the other who died on treatment at 13 months from transformed disease. Both of these patients had high Ki-67 levels.

Grade 3 or 4 hematological adverse events were neutropenia in four patients, and thrombocytopenia in two patients. There were no cases of grade 3 or 4 anemia.

Grade 3 or 4 nonhematological adverse events were fatigue, myalgia, and atrial fibrillation in seven patients each, diarrhea in six patients, and petechiae/bleeding in three patients.

Patients will continue to be followed for late adverse events, secondary cancers, and relapses, and further studies on clonal evolution, mutation profiling, and MRD are ongoing and will be reported at a later date, Dr. Jain said.

The National Cancer Institute supported the study. Dr. Jain reported having no financial disclosures.

SOURCE: Jain P et al. 15-ICML. Abstract 011.

LUGANO, SWITZERLAND – The chemotherapy-free combination of ibrutinib (Imbruvica) and rituximab is highly effective as frontline therapy for older, transplant-ineligible patients with nonblastoid mantle cell lymphoma, according to investigators.

Neil Osterweil/MDedge News

In a phase 2 study of patients with a median age of 71 years, 38 of 41 patients (93%) had an objective response, and the regimen was both safe and easy to administer, reported Preetesh Jain, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

“The adverse event profile was generally favorable, with specific monitoring recommended for patients with cardiovascular comorbidities and a history of atrial fibrillation,” he said at the International Conference on Malignant Lymphoma.

The investigators enrolled 48 patients aged 65 years and older with previously untreated mantle cell lymphoma (MCL), of whom 41 were evaluable for the primary endpoints of overall response rate (ORR) and safety. The patients had good performance status and normal organ function, with the largest tumor size less than 10 cm. Patients with atrial fibrillation could participate, if the fibrillation was controlled. Patients with Ki-67 protein levels of 50% or greater and blastoid/pleomorphic histology were excluded.

Patients were treated with ibrutinib 560 mg orally daily for each 28-day cycle, with therapy continued until disease progression, or until therapy was stopped for any other reason. Patients also received intravenous rituximab 375 mg/m² on days 1, 8, 15 and 22, plus or minus one day for cycle 1, on day 1 of cycles 3-8, and on day 1 of every other cycle for up to 2 years.

Of the 41 patients evaluable for response, 26 (64%) had a complete response (CR) and 12 (29%) had a partial response. Three additional patients had stable disease, for an objective response rate of 93%.

Of 34 patients with PET scans, all had negative scans. Of 37 patients evaluable for minimal residual disease (MRD) by flow cytometry, 21 (58%) were MRD negative.

Patients with low or intermediate Mantle Cell Lymphoma International Prognostic Index (MIPI) scores had a higher ORR (100% vs. 89% for patients with high MIPI scores), and patients with low Ki-67 levels had a higher response rate than that of patients with KI-67 of 30% or greater (80% vs. 87%).

Neither median 3-year progression-free survival nor median 3-year overall survival have been reached, with respective 3-year rates of 87% and 95%.

Four patients experienced disease progression at 4, 10, 13 and 33 months of treatment. Three of these patients had disease that had transformed to blastoid/pleomorphic variant, two had Ki-67 of 30% or greater, one had mutations in TP53, and one had FAT1 and SF3B1 mutations.


Two patients died after ibrutinib therapy, one who had discontinued therapy because of bleeding, and the other who died on treatment at 13 months from transformed disease. Both of these patients had high Ki-67 levels.

Grade 3 or 4 hematological adverse events were neutropenia in four patients, and thrombocytopenia in two patients. There were no cases of grade 3 or 4 anemia.

Grade 3 or 4 nonhematological adverse events were fatigue, myalgia, and atrial fibrillation in seven patients each, diarrhea in six patients, and petechiae/bleeding in three patients.

Patients will continue to be followed for late adverse events, secondary cancers, and relapses, and further studies on clonal evolution, mutation profiling, and MRD are ongoing and will be reported at a later date, Dr. Jain said.

The National Cancer Institute supported the study. Dr. Jain reported having no financial disclosures.

SOURCE: Jain P et al. 15-ICML. Abstract 011.

LUGANO, SWITZERLAND – The chemotherapy-free combination of ibrutinib (Imbruvica) and rituximab is highly effective as frontline therapy for older, transplant-ineligible patients with nonblastoid mantle cell lymphoma, according to investigators.

Neil Osterweil/MDedge News

In a phase 2 study of patients with a median age of 71 years, 38 of 41 patients (93%) had an objective response, and the regimen was both safe and easy to administer, reported Preetesh Jain, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

“The adverse event profile was generally favorable, with specific monitoring recommended for patients with cardiovascular comorbidities and a history of atrial fibrillation,” he said at the International Conference on Malignant Lymphoma.

The investigators enrolled 48 patients aged 65 years and older with previously untreated mantle cell lymphoma (MCL), of whom 41 were evaluable for the primary endpoints of overall response rate (ORR) and safety. The patients had good performance status and normal organ function, with the largest tumor size less than 10 cm. Patients with atrial fibrillation could participate, if the fibrillation was controlled. Patients with Ki-67 protein levels of 50% or greater and blastoid/pleomorphic histology were excluded.

Patients were treated with ibrutinib 560 mg orally daily for each 28-day cycle, with therapy continued until disease progression, or until therapy was stopped for any other reason. Patients also received intravenous rituximab 375 mg/m² on days 1, 8, 15 and 22, plus or minus one day for cycle 1, on day 1 of cycles 3-8, and on day 1 of every other cycle for up to 2 years.

Of the 41 patients evaluable for response, 26 (64%) had a complete response (CR) and 12 (29%) had a partial response. Three additional patients had stable disease, for an objective response rate of 93%.

Of 34 patients with PET scans, all had negative scans. Of 37 patients evaluable for minimal residual disease (MRD) by flow cytometry, 21 (58%) were MRD negative.

Patients with low or intermediate Mantle Cell Lymphoma International Prognostic Index (MIPI) scores had a higher ORR (100% vs. 89% for patients with high MIPI scores), and patients with low Ki-67 levels had a higher response rate than that of patients with KI-67 of 30% or greater (80% vs. 87%).

Neither median 3-year progression-free survival nor median 3-year overall survival have been reached, with respective 3-year rates of 87% and 95%.

Four patients experienced disease progression at 4, 10, 13 and 33 months of treatment. Three of these patients had disease that had transformed to blastoid/pleomorphic variant, two had Ki-67 of 30% or greater, one had mutations in TP53, and one had FAT1 and SF3B1 mutations.


Two patients died after ibrutinib therapy, one who had discontinued therapy because of bleeding, and the other who died on treatment at 13 months from transformed disease. Both of these patients had high Ki-67 levels.

Grade 3 or 4 hematological adverse events were neutropenia in four patients, and thrombocytopenia in two patients. There were no cases of grade 3 or 4 anemia.

Grade 3 or 4 nonhematological adverse events were fatigue, myalgia, and atrial fibrillation in seven patients each, diarrhea in six patients, and petechiae/bleeding in three patients.

Patients will continue to be followed for late adverse events, secondary cancers, and relapses, and further studies on clonal evolution, mutation profiling, and MRD are ongoing and will be reported at a later date, Dr. Jain said.

The National Cancer Institute supported the study. Dr. Jain reported having no financial disclosures.

SOURCE: Jain P et al. 15-ICML. Abstract 011.

Low-dose radiation therapy – with or without concurrent chemotherapy – appears promising as a treatment for patients with relapsed or refractory mantle cell lymphoma (MCL) or at least a bridge to subsequent therapy, according to findings published in Blood Advances.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

Matthew S. Ning, MD, of the department of radiation oncology at the University of Texas MD Anderson Cancer Center, Houston, and colleagues, said this is the first study to evaluate low-dose radiation therapy (LDRT) with chemotherapy as a treatment modality outside of palliative care for relapsed, multiple refractory MCL patients.

“Our findings indicate that LDRT imparts excellent [local control], minimal toxicity, and favorable outcomes in this setting,” the researchers said.

The study included 19 patients with a total of 98 sites of relapsed, refractory MCL who were treated from 2014 to 2018. The median follow-up was 51.3 months from initial diagnosis and 15.4 months from initial treatment with low-dose radiation therapy, given at a dose of 4 Gy.

These were hard-to-treat patients who had received multiple prior therapies since diagnosis, including carfilzomib, ibrutinib, bortezomib, anthracycline, and rituximab. In total, 8 of the patients had previously undergone autologous stem cell transplant and 11 were refractory to ibrutinib by the time of initial radiation therapy.

Median age of the patients was 69 years; 15 patients had classical histology and 4 had blastoid variant. Among the 98 tumor sites treated, the median tumor size was 2.8 cm.

In all, 14 patients received initial LDRT that was concurrent with chemotherapy. The remaining 5 patients had stopped chemotherapy prior to starting LDRT.

LDRT was given in 1-2 daily fractions via 3-dimensional conformal radiation therapy or electron beam.

Of the 98 tumor sites treated, complete response was achieved for 79 sites (81%) and the median time to complete response was 2.7 months after the start of LDRT. The researchers removed one patient who was an outlier with 27 tumor sites treated, and that dropped the complete response rate down to 76%. The overall response rate, which include an additional five sites with partial response, was 86%.

The researchers found links between complete response and soft tissue site versus non–soft tissue site (hazard ratio, 1.80; 1.12-2.90, P = .02). However, there were no associations between response and chemo-refractory status, ibrutinib-refractory status, prior chemotherapy courts, receipt of concurrent chemotherapy, tumor size, number of fractions, lesions treated per course, or blastoid variant.

The overall survival at 1 year after LDRT initiation was 90% and the 1-year progression-free survival was 55%. All five patients who died were refractory to ibrutinib.

The researchers reported finding no radiation therapy–related toxicities, even when patients received concurrent chemotherapy.

The use of LDRT has the potential to bridge refractory patients to subsequent therapies or to provide treatment breaks as patients recover from toxicities, the researchers said. However, they called for additional studies to confirm that this approach improves progression-free survival over chemotherapy alone.

The study was supported in part by a grant from the National Cancer Institute. The researchers reported having no competing financial interests.

[email protected]

SOURCE: Ning MS et al. Blood Adv. 2019. Jul 9;3(13):2035-9.

Low-dose radiation therapy – with or without concurrent chemotherapy – appears promising as a treatment for patients with relapsed or refractory mantle cell lymphoma (MCL) or at least a bridge to subsequent therapy, according to findings published in Blood Advances.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

Matthew S. Ning, MD, of the department of radiation oncology at the University of Texas MD Anderson Cancer Center, Houston, and colleagues, said this is the first study to evaluate low-dose radiation therapy (LDRT) with chemotherapy as a treatment modality outside of palliative care for relapsed, multiple refractory MCL patients.

“Our findings indicate that LDRT imparts excellent [local control], minimal toxicity, and favorable outcomes in this setting,” the researchers said.

The study included 19 patients with a total of 98 sites of relapsed, refractory MCL who were treated from 2014 to 2018. The median follow-up was 51.3 months from initial diagnosis and 15.4 months from initial treatment with low-dose radiation therapy, given at a dose of 4 Gy.

These were hard-to-treat patients who had received multiple prior therapies since diagnosis, including carfilzomib, ibrutinib, bortezomib, anthracycline, and rituximab. In total, 8 of the patients had previously undergone autologous stem cell transplant and 11 were refractory to ibrutinib by the time of initial radiation therapy.

Median age of the patients was 69 years; 15 patients had classical histology and 4 had blastoid variant. Among the 98 tumor sites treated, the median tumor size was 2.8 cm.

In all, 14 patients received initial LDRT that was concurrent with chemotherapy. The remaining 5 patients had stopped chemotherapy prior to starting LDRT.

LDRT was given in 1-2 daily fractions via 3-dimensional conformal radiation therapy or electron beam.

Of the 98 tumor sites treated, complete response was achieved for 79 sites (81%) and the median time to complete response was 2.7 months after the start of LDRT. The researchers removed one patient who was an outlier with 27 tumor sites treated, and that dropped the complete response rate down to 76%. The overall response rate, which include an additional five sites with partial response, was 86%.

The researchers found links between complete response and soft tissue site versus non–soft tissue site (hazard ratio, 1.80; 1.12-2.90, P = .02). However, there were no associations between response and chemo-refractory status, ibrutinib-refractory status, prior chemotherapy courts, receipt of concurrent chemotherapy, tumor size, number of fractions, lesions treated per course, or blastoid variant.

The overall survival at 1 year after LDRT initiation was 90% and the 1-year progression-free survival was 55%. All five patients who died were refractory to ibrutinib.

The researchers reported finding no radiation therapy–related toxicities, even when patients received concurrent chemotherapy.

The use of LDRT has the potential to bridge refractory patients to subsequent therapies or to provide treatment breaks as patients recover from toxicities, the researchers said. However, they called for additional studies to confirm that this approach improves progression-free survival over chemotherapy alone.

The study was supported in part by a grant from the National Cancer Institute. The researchers reported having no competing financial interests.

[email protected]

SOURCE: Ning MS et al. Blood Adv. 2019. Jul 9;3(13):2035-9.

Low-dose radiation therapy – with or without concurrent chemotherapy – appears promising as a treatment for patients with relapsed or refractory mantle cell lymphoma (MCL) or at least a bridge to subsequent therapy, according to findings published in Blood Advances.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

Matthew S. Ning, MD, of the department of radiation oncology at the University of Texas MD Anderson Cancer Center, Houston, and colleagues, said this is the first study to evaluate low-dose radiation therapy (LDRT) with chemotherapy as a treatment modality outside of palliative care for relapsed, multiple refractory MCL patients.

“Our findings indicate that LDRT imparts excellent [local control], minimal toxicity, and favorable outcomes in this setting,” the researchers said.

The study included 19 patients with a total of 98 sites of relapsed, refractory MCL who were treated from 2014 to 2018. The median follow-up was 51.3 months from initial diagnosis and 15.4 months from initial treatment with low-dose radiation therapy, given at a dose of 4 Gy.

These were hard-to-treat patients who had received multiple prior therapies since diagnosis, including carfilzomib, ibrutinib, bortezomib, anthracycline, and rituximab. In total, 8 of the patients had previously undergone autologous stem cell transplant and 11 were refractory to ibrutinib by the time of initial radiation therapy.

Median age of the patients was 69 years; 15 patients had classical histology and 4 had blastoid variant. Among the 98 tumor sites treated, the median tumor size was 2.8 cm.

In all, 14 patients received initial LDRT that was concurrent with chemotherapy. The remaining 5 patients had stopped chemotherapy prior to starting LDRT.

LDRT was given in 1-2 daily fractions via 3-dimensional conformal radiation therapy or electron beam.

Of the 98 tumor sites treated, complete response was achieved for 79 sites (81%) and the median time to complete response was 2.7 months after the start of LDRT. The researchers removed one patient who was an outlier with 27 tumor sites treated, and that dropped the complete response rate down to 76%. The overall response rate, which include an additional five sites with partial response, was 86%.

The researchers found links between complete response and soft tissue site versus non–soft tissue site (hazard ratio, 1.80; 1.12-2.90, P = .02). However, there were no associations between response and chemo-refractory status, ibrutinib-refractory status, prior chemotherapy courts, receipt of concurrent chemotherapy, tumor size, number of fractions, lesions treated per course, or blastoid variant.

The overall survival at 1 year after LDRT initiation was 90% and the 1-year progression-free survival was 55%. All five patients who died were refractory to ibrutinib.

The researchers reported finding no radiation therapy–related toxicities, even when patients received concurrent chemotherapy.

The use of LDRT has the potential to bridge refractory patients to subsequent therapies or to provide treatment breaks as patients recover from toxicities, the researchers said. However, they called for additional studies to confirm that this approach improves progression-free survival over chemotherapy alone.

The study was supported in part by a grant from the National Cancer Institute. The researchers reported having no competing financial interests.

[email protected]

SOURCE: Ning MS et al. Blood Adv. 2019. Jul 9;3(13):2035-9.

Flavopiridol – also known as alvocidib – showed minimal clinical response in patients with relapsed or refractory mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and other B-cell lymphomas, according to results from a single-center, phase 1/2 trial.

“Promising preclinical data in cell lines derived from MCL and activated DLBCL led to a series of clinical trials of flavopiridol in various hematological malignancies,” wrote Milos D. Miljković, MD, and colleagues in the lymphoid malignancies branch of the National Cancer Institute in Bethesda, Md. The findings were published in a letter to the editor in Leukemia & Lymphoma.

The study included 28 patients with relapsed/refractory MCL, DLBCL, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma who received a hybrid dosing regimen of the novel CDK inhibitor. Flavopiridol was administered as a 30-minute bolus, followed by a 4-hour infusion.

The researchers used an intrapatient dose escalation between the first and successive cycles, in addition to a three-plus-three interpatient escalation, to lessen the risk of tumor lysis syndrome (TLS).

The primary outcomes were the clinical response rate, maximum tolerated dose, dose-limiting toxicities, and toxicity profile of the hybrid dosing regimen.

Of 26 evaluable patients, one patient with DLBCL maintained a partial response for 84 days (overall response rate, 3.8%). One patient with MCL had a 50% decrease in the size of target lesions at 2 months, but this was not sustained at 4 months. In total, nine patients had stable disease for a disease control rate of 38.4%.

“[Flavopiridol] had minimal efficacy in patients with relapsed/refractory non-Hodgkin B-cell lymphoma, casting doubt on the utility of CDK inhibition in this disease,” the researchers wrote.

With respect to safety, there were eight dose-limiting toxicities reported in three patients. These included grade 3 TLS, elevated transaminase levels, hypoalbuminemia, hyperkalemia, non-neutropenic infection, and grade 4 metabolic acidosis and gastrointestinal perforation.

The most common treatment-related toxicities were hematologic, including neutropenia, anemia, thrombocytopenia, leukocytosis, and lymphopenia.

Dr. Miljković and colleagues noted that CDK inhibitor therapy may elicit better responses when used in combination with other agents.

“Ongoing trials of more specific CDK inhibitors in combination with other agents will help elucidate their role in lymphoma treatment,” they wrote.

The trial is sponsored by the National Cancer Institute and the study authors are employees of the National Cancer Institute.

SOURCE: Miljkovic MD et al. Leuk Lymphoma. 2019 Jun 17. doi: 10.1080/10428194.2019.1627540.

Flavopiridol – also known as alvocidib – showed minimal clinical response in patients with relapsed or refractory mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and other B-cell lymphomas, according to results from a single-center, phase 1/2 trial.

“Promising preclinical data in cell lines derived from MCL and activated DLBCL led to a series of clinical trials of flavopiridol in various hematological malignancies,” wrote Milos D. Miljković, MD, and colleagues in the lymphoid malignancies branch of the National Cancer Institute in Bethesda, Md. The findings were published in a letter to the editor in Leukemia & Lymphoma.

The study included 28 patients with relapsed/refractory MCL, DLBCL, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma who received a hybrid dosing regimen of the novel CDK inhibitor. Flavopiridol was administered as a 30-minute bolus, followed by a 4-hour infusion.

The researchers used an intrapatient dose escalation between the first and successive cycles, in addition to a three-plus-three interpatient escalation, to lessen the risk of tumor lysis syndrome (TLS).

The primary outcomes were the clinical response rate, maximum tolerated dose, dose-limiting toxicities, and toxicity profile of the hybrid dosing regimen.

Of 26 evaluable patients, one patient with DLBCL maintained a partial response for 84 days (overall response rate, 3.8%). One patient with MCL had a 50% decrease in the size of target lesions at 2 months, but this was not sustained at 4 months. In total, nine patients had stable disease for a disease control rate of 38.4%.

“[Flavopiridol] had minimal efficacy in patients with relapsed/refractory non-Hodgkin B-cell lymphoma, casting doubt on the utility of CDK inhibition in this disease,” the researchers wrote.

With respect to safety, there were eight dose-limiting toxicities reported in three patients. These included grade 3 TLS, elevated transaminase levels, hypoalbuminemia, hyperkalemia, non-neutropenic infection, and grade 4 metabolic acidosis and gastrointestinal perforation.

The most common treatment-related toxicities were hematologic, including neutropenia, anemia, thrombocytopenia, leukocytosis, and lymphopenia.

Dr. Miljković and colleagues noted that CDK inhibitor therapy may elicit better responses when used in combination with other agents.

“Ongoing trials of more specific CDK inhibitors in combination with other agents will help elucidate their role in lymphoma treatment,” they wrote.

The trial is sponsored by the National Cancer Institute and the study authors are employees of the National Cancer Institute.

SOURCE: Miljkovic MD et al. Leuk Lymphoma. 2019 Jun 17. doi: 10.1080/10428194.2019.1627540.

Flavopiridol – also known as alvocidib – showed minimal clinical response in patients with relapsed or refractory mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and other B-cell lymphomas, according to results from a single-center, phase 1/2 trial.

“Promising preclinical data in cell lines derived from MCL and activated DLBCL led to a series of clinical trials of flavopiridol in various hematological malignancies,” wrote Milos D. Miljković, MD, and colleagues in the lymphoid malignancies branch of the National Cancer Institute in Bethesda, Md. The findings were published in a letter to the editor in Leukemia & Lymphoma.

The study included 28 patients with relapsed/refractory MCL, DLBCL, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma who received a hybrid dosing regimen of the novel CDK inhibitor. Flavopiridol was administered as a 30-minute bolus, followed by a 4-hour infusion.

The researchers used an intrapatient dose escalation between the first and successive cycles, in addition to a three-plus-three interpatient escalation, to lessen the risk of tumor lysis syndrome (TLS).

The primary outcomes were the clinical response rate, maximum tolerated dose, dose-limiting toxicities, and toxicity profile of the hybrid dosing regimen.

Of 26 evaluable patients, one patient with DLBCL maintained a partial response for 84 days (overall response rate, 3.8%). One patient with MCL had a 50% decrease in the size of target lesions at 2 months, but this was not sustained at 4 months. In total, nine patients had stable disease for a disease control rate of 38.4%.

“[Flavopiridol] had minimal efficacy in patients with relapsed/refractory non-Hodgkin B-cell lymphoma, casting doubt on the utility of CDK inhibition in this disease,” the researchers wrote.

With respect to safety, there were eight dose-limiting toxicities reported in three patients. These included grade 3 TLS, elevated transaminase levels, hypoalbuminemia, hyperkalemia, non-neutropenic infection, and grade 4 metabolic acidosis and gastrointestinal perforation.

The most common treatment-related toxicities were hematologic, including neutropenia, anemia, thrombocytopenia, leukocytosis, and lymphopenia.

Dr. Miljković and colleagues noted that CDK inhibitor therapy may elicit better responses when used in combination with other agents.

“Ongoing trials of more specific CDK inhibitors in combination with other agents will help elucidate their role in lymphoma treatment,” they wrote.

The trial is sponsored by the National Cancer Institute and the study authors are employees of the National Cancer Institute.

SOURCE: Miljkovic MD et al. Leuk Lymphoma. 2019 Jun 17. doi: 10.1080/10428194.2019.1627540.

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

Amsterdam – For patients with untreated mantle cell lymphoma (MCL), the anti-CD20 monoclonal antibody obinutuzumab may one day offer an alternative to rituximab, according to investigators.

Patients in the LYMA-101 trial were given four cycles of obinutuzumab in combination with dexamethasone, high-dose aracytine, and platinum chemotherapy (O-DHAP), followed by autologous stem cell transplantation (ASCT) and maintenance obinutuzumab. After a median follow-up of 14.6 months, ranging from 3.8 to 24.4 months, 85% of evaluable patients had achieved minimal residual disease (MRD) in bone marrow, reported lead author Steven Le Gouill, MD, PhD, of the University Hospital of Nantes, and his colleagues.

In this disease population, an MRD rate of 85% is “unprecedented,” Dr. Le Gouill said during his presentation at the annual congress of the European Hematology Association. Based on findings from LYMA-101 and preclinical data, Dr. Le Gouill suggested that obinutuzumab may become an alternative to rituximab, the current standard anti-CD20 antibody.

“There are few data of interest for obinutuzumab in MCL, but there is a strong rationale in the lab as obinutuzumab has a different mechanism of action against tumor cells [than rituximab], with more efficacy against MCL cells,” Dr. Le Gouill said.

Data from the ongoing phase 2 trial were drawn from 85 patients with untreated MCL who were 65 years or younger at the time of enrollment. More specifically, median patient age was 55.5 years and 17.4% of patients had blastoid disease. All patients were given the O-DHAP/ASCT/obinutuzumab protocol, with a maintenance period of 3 years. Thereafter, MRD-positive patients may receive obinutuzumab on-demand.

The primary endpoint was MRD in bone marrow after induction therapy, measured by quantitative PCR (qPCR) and droplet digital PCR (ddPCR). Secondary endpoints included response rates, survival measures, incidence of stem cell collection failure after O-DHAP, and MRD rates at additional therapeutic time points.

Owing to the ongoing nature of the study, Dr. Le Gouill focused on the primary endpoint during his presentation.

Analysis showed that 75% and 85% of evaluable patients had achieved negative MRD in bone marrow after induction, according to qPCR and ddPCR, respectively.

These early findings give “a flavor of the results in terms of efficacy,” Dr. Le Gouill said, noting that “the median follow-up is pretty short.”

Still, 1-year findings were “very promising,” he said, with a progression-free survival of 93.4% and overall survival of 96%.

Twelve patients stopped treatment before ASCT, three prior to maintenance, and nine during maintenance. Of these 24 patients, 13 stopped treatment because of adverse events. The remaining 11 patients halted therapy because of disease progression, other malignancies, or death.

From the original 85 patients, 3 patients died and 3 progressed. Considering all of these findings, and that no major toxicities were encountered, the investigators concluded that the regimen was safe.

Overall, the results suggest that further research is needed, Dr. Le Gouill concluded. “Maybe this is where obinutuzumab may have stronger efficacy in MCL, as compared to rituximab,” he said.

The study is sponsored by the Lymphoma Academic Research Organisation. The investigators reported relationships with Roche, Janssen-Cilag, Gilead, Servier, and Novartis.

SOURCE: Le Gouill S et al. EHA Congress, Abstract S103.

Amsterdam – For patients with untreated mantle cell lymphoma (MCL), the anti-CD20 monoclonal antibody obinutuzumab may one day offer an alternative to rituximab, according to investigators.

Patients in the LYMA-101 trial were given four cycles of obinutuzumab in combination with dexamethasone, high-dose aracytine, and platinum chemotherapy (O-DHAP), followed by autologous stem cell transplantation (ASCT) and maintenance obinutuzumab. After a median follow-up of 14.6 months, ranging from 3.8 to 24.4 months, 85% of evaluable patients had achieved minimal residual disease (MRD) in bone marrow, reported lead author Steven Le Gouill, MD, PhD, of the University Hospital of Nantes, and his colleagues.

In this disease population, an MRD rate of 85% is “unprecedented,” Dr. Le Gouill said during his presentation at the annual congress of the European Hematology Association. Based on findings from LYMA-101 and preclinical data, Dr. Le Gouill suggested that obinutuzumab may become an alternative to rituximab, the current standard anti-CD20 antibody.

“There are few data of interest for obinutuzumab in MCL, but there is a strong rationale in the lab as obinutuzumab has a different mechanism of action against tumor cells [than rituximab], with more efficacy against MCL cells,” Dr. Le Gouill said.

Data from the ongoing phase 2 trial were drawn from 85 patients with untreated MCL who were 65 years or younger at the time of enrollment. More specifically, median patient age was 55.5 years and 17.4% of patients had blastoid disease. All patients were given the O-DHAP/ASCT/obinutuzumab protocol, with a maintenance period of 3 years. Thereafter, MRD-positive patients may receive obinutuzumab on-demand.

The primary endpoint was MRD in bone marrow after induction therapy, measured by quantitative PCR (qPCR) and droplet digital PCR (ddPCR). Secondary endpoints included response rates, survival measures, incidence of stem cell collection failure after O-DHAP, and MRD rates at additional therapeutic time points.

Owing to the ongoing nature of the study, Dr. Le Gouill focused on the primary endpoint during his presentation.

Analysis showed that 75% and 85% of evaluable patients had achieved negative MRD in bone marrow after induction, according to qPCR and ddPCR, respectively.

These early findings give “a flavor of the results in terms of efficacy,” Dr. Le Gouill said, noting that “the median follow-up is pretty short.”

Still, 1-year findings were “very promising,” he said, with a progression-free survival of 93.4% and overall survival of 96%.

Twelve patients stopped treatment before ASCT, three prior to maintenance, and nine during maintenance. Of these 24 patients, 13 stopped treatment because of adverse events. The remaining 11 patients halted therapy because of disease progression, other malignancies, or death.

From the original 85 patients, 3 patients died and 3 progressed. Considering all of these findings, and that no major toxicities were encountered, the investigators concluded that the regimen was safe.

Overall, the results suggest that further research is needed, Dr. Le Gouill concluded. “Maybe this is where obinutuzumab may have stronger efficacy in MCL, as compared to rituximab,” he said.

The study is sponsored by the Lymphoma Academic Research Organisation. The investigators reported relationships with Roche, Janssen-Cilag, Gilead, Servier, and Novartis.

SOURCE: Le Gouill S et al. EHA Congress, Abstract S103.

Amsterdam – For patients with untreated mantle cell lymphoma (MCL), the anti-CD20 monoclonal antibody obinutuzumab may one day offer an alternative to rituximab, according to investigators.

Patients in the LYMA-101 trial were given four cycles of obinutuzumab in combination with dexamethasone, high-dose aracytine, and platinum chemotherapy (O-DHAP), followed by autologous stem cell transplantation (ASCT) and maintenance obinutuzumab. After a median follow-up of 14.6 months, ranging from 3.8 to 24.4 months, 85% of evaluable patients had achieved minimal residual disease (MRD) in bone marrow, reported lead author Steven Le Gouill, MD, PhD, of the University Hospital of Nantes, and his colleagues.

In this disease population, an MRD rate of 85% is “unprecedented,” Dr. Le Gouill said during his presentation at the annual congress of the European Hematology Association. Based on findings from LYMA-101 and preclinical data, Dr. Le Gouill suggested that obinutuzumab may become an alternative to rituximab, the current standard anti-CD20 antibody.

“There are few data of interest for obinutuzumab in MCL, but there is a strong rationale in the lab as obinutuzumab has a different mechanism of action against tumor cells [than rituximab], with more efficacy against MCL cells,” Dr. Le Gouill said.

Data from the ongoing phase 2 trial were drawn from 85 patients with untreated MCL who were 65 years or younger at the time of enrollment. More specifically, median patient age was 55.5 years and 17.4% of patients had blastoid disease. All patients were given the O-DHAP/ASCT/obinutuzumab protocol, with a maintenance period of 3 years. Thereafter, MRD-positive patients may receive obinutuzumab on-demand.

The primary endpoint was MRD in bone marrow after induction therapy, measured by quantitative PCR (qPCR) and droplet digital PCR (ddPCR). Secondary endpoints included response rates, survival measures, incidence of stem cell collection failure after O-DHAP, and MRD rates at additional therapeutic time points.

Owing to the ongoing nature of the study, Dr. Le Gouill focused on the primary endpoint during his presentation.

Analysis showed that 75% and 85% of evaluable patients had achieved negative MRD in bone marrow after induction, according to qPCR and ddPCR, respectively.

These early findings give “a flavor of the results in terms of efficacy,” Dr. Le Gouill said, noting that “the median follow-up is pretty short.”

Still, 1-year findings were “very promising,” he said, with a progression-free survival of 93.4% and overall survival of 96%.

Twelve patients stopped treatment before ASCT, three prior to maintenance, and nine during maintenance. Of these 24 patients, 13 stopped treatment because of adverse events. The remaining 11 patients halted therapy because of disease progression, other malignancies, or death.

From the original 85 patients, 3 patients died and 3 progressed. Considering all of these findings, and that no major toxicities were encountered, the investigators concluded that the regimen was safe.

Overall, the results suggest that further research is needed, Dr. Le Gouill concluded. “Maybe this is where obinutuzumab may have stronger efficacy in MCL, as compared to rituximab,” he said.

The study is sponsored by the Lymphoma Academic Research Organisation. The investigators reported relationships with Roche, Janssen-Cilag, Gilead, Servier, and Novartis.

SOURCE: Le Gouill S et al. EHA Congress, Abstract S103.

In a large cohort of patients with mantle cell lymphoma (MCL), CD23 expression was associated with significantly improved survival outcomes, according to a retrospective analysis.

“Mantle cell lymphoma has a distinctive immunophenotype, typically positive for pan B-cell markers, CD5 and cyclin D1, but negative for CD10, CD23, and CD200. Although most cases show this immunophenotype, some MCL cases have atypical immunophenotypic features, such as expression of CD10, CD23, or rarely CD200 or lack of expression of CD5,” wrote Annapurna Saksena, MD, of MD Anderson Cancer Center, Houston, and colleagues. Their report is in Human Pathology.

They retrospectively reviewed medical records from a pathology database at MD Anderson from the period of 2008-2016. In all, 798 patients with MCL were identified, of which 103 were classified as CD23-positive via flow cytometry.

The team collected data related to the immunophenotypic and clinicopathologic characteristics of the disease, in addition to survival-related outcomes, including progression-free survival (PFS) and overall survival (OS). They compared outcomes for the CD23-positive group against 240 patients with CD23-negative MCL.

After analysis, Dr. Saksena and colleagues found that patients with CD23-positive MCL more frequently had bone marrow involvement (89% vs. 78%, P = .02), a leukemic nonnodal presentation (42% vs. 11%, P = .0001), an elevated leukocyte count (33% vs. 18%, P = .009), and stage 4 disease (87% vs. 77%, P = .03).

The researchers reported that CD23 expression was associated with significantly improved PFS and OS (P = .029 and P = .02, respectively) in the univariate analysis.

However, the prognostic significance was partially lost when leukemic nonnodal cases were excluded, the researchers reported.

In addition to the higher frequency of leukemic nonnodal presentation with CD23-positive MCL cases, there was a higher frequency of CD200 expression and a lower frequency of SOX11 expression.

The researchers acknowledged that a key limitation of the study was the loss of prognostic significance in the multivariate analysis. Further studies are needed to fully understand the links between CD23 expression and MCL survival, they noted.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Saksena A et al. Hum Pathol. 2019 May 2. doi: 10.1016/j.humpath.2019.04.010.

In a large cohort of patients with mantle cell lymphoma (MCL), CD23 expression was associated with significantly improved survival outcomes, according to a retrospective analysis.

“Mantle cell lymphoma has a distinctive immunophenotype, typically positive for pan B-cell markers, CD5 and cyclin D1, but negative for CD10, CD23, and CD200. Although most cases show this immunophenotype, some MCL cases have atypical immunophenotypic features, such as expression of CD10, CD23, or rarely CD200 or lack of expression of CD5,” wrote Annapurna Saksena, MD, of MD Anderson Cancer Center, Houston, and colleagues. Their report is in Human Pathology.

They retrospectively reviewed medical records from a pathology database at MD Anderson from the period of 2008-2016. In all, 798 patients with MCL were identified, of which 103 were classified as CD23-positive via flow cytometry.

The team collected data related to the immunophenotypic and clinicopathologic characteristics of the disease, in addition to survival-related outcomes, including progression-free survival (PFS) and overall survival (OS). They compared outcomes for the CD23-positive group against 240 patients with CD23-negative MCL.

After analysis, Dr. Saksena and colleagues found that patients with CD23-positive MCL more frequently had bone marrow involvement (89% vs. 78%, P = .02), a leukemic nonnodal presentation (42% vs. 11%, P = .0001), an elevated leukocyte count (33% vs. 18%, P = .009), and stage 4 disease (87% vs. 77%, P = .03).

The researchers reported that CD23 expression was associated with significantly improved PFS and OS (P = .029 and P = .02, respectively) in the univariate analysis.

However, the prognostic significance was partially lost when leukemic nonnodal cases were excluded, the researchers reported.

In addition to the higher frequency of leukemic nonnodal presentation with CD23-positive MCL cases, there was a higher frequency of CD200 expression and a lower frequency of SOX11 expression.

The researchers acknowledged that a key limitation of the study was the loss of prognostic significance in the multivariate analysis. Further studies are needed to fully understand the links between CD23 expression and MCL survival, they noted.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Saksena A et al. Hum Pathol. 2019 May 2. doi: 10.1016/j.humpath.2019.04.010.

In a large cohort of patients with mantle cell lymphoma (MCL), CD23 expression was associated with significantly improved survival outcomes, according to a retrospective analysis.

“Mantle cell lymphoma has a distinctive immunophenotype, typically positive for pan B-cell markers, CD5 and cyclin D1, but negative for CD10, CD23, and CD200. Although most cases show this immunophenotype, some MCL cases have atypical immunophenotypic features, such as expression of CD10, CD23, or rarely CD200 or lack of expression of CD5,” wrote Annapurna Saksena, MD, of MD Anderson Cancer Center, Houston, and colleagues. Their report is in Human Pathology.

They retrospectively reviewed medical records from a pathology database at MD Anderson from the period of 2008-2016. In all, 798 patients with MCL were identified, of which 103 were classified as CD23-positive via flow cytometry.

The team collected data related to the immunophenotypic and clinicopathologic characteristics of the disease, in addition to survival-related outcomes, including progression-free survival (PFS) and overall survival (OS). They compared outcomes for the CD23-positive group against 240 patients with CD23-negative MCL.

After analysis, Dr. Saksena and colleagues found that patients with CD23-positive MCL more frequently had bone marrow involvement (89% vs. 78%, P = .02), a leukemic nonnodal presentation (42% vs. 11%, P = .0001), an elevated leukocyte count (33% vs. 18%, P = .009), and stage 4 disease (87% vs. 77%, P = .03).

The researchers reported that CD23 expression was associated with significantly improved PFS and OS (P = .029 and P = .02, respectively) in the univariate analysis.

However, the prognostic significance was partially lost when leukemic nonnodal cases were excluded, the researchers reported.

In addition to the higher frequency of leukemic nonnodal presentation with CD23-positive MCL cases, there was a higher frequency of CD200 expression and a lower frequency of SOX11 expression.

The researchers acknowledged that a key limitation of the study was the loss of prognostic significance in the multivariate analysis. Further studies are needed to fully understand the links between CD23 expression and MCL survival, they noted.

No funding sources were reported. The authors reported having no conflicts of interest.

SOURCE: Saksena A et al. Hum Pathol. 2019 May 2. doi: 10.1016/j.humpath.2019.04.010.

An atypical case of cutaneous mantle cell lymphoma (MCL) with histomorphological features mimicking subcutaneous panniculitis-like T-cell lymphoma (SPTCL) highlights a “potential pitfall,” according to investigators.

This unusual case stresses the importance of molecular cytogenetics and/or immunohistochemistry for panniculitis-type lymphomas, reported lead author Caroline Laggis, MD of the University of Utah, Salt Lake City, and colleagues.

“While morphologic features of SPTCL, specifically rimming of adipocytes by neoplastic lymphoid cells, have been documented in other types of lymphomas, this case is exceptional in that the morphologic features of SPTCL are showed in secondary cutaneous involvement by MCL,” the investigators wrote. Their report is in Journal of Cutaneous Pathology.

The patient was a 69-year-old man who presented with 2-year history of night sweats and fever of unknown origin, and, closer to presentation, weight loss and tender bumps under the skin of his pelvic region.

Subsequent computed tomography and excisional lymph node biopsy led to a diagnosis of MCL, with a Mantle Cell Lymphoma International Prognostic Index of 5, suggesting aggressive, intermediate-risk disease. Further imaging showed involvement of the nasopharynx, and cervical and mediastinal lymph nodes.

Bendamustine and rituximab chemotherapy was given unremarkably until the final cycle, at which point the patient presented with tender subcutaneous nodules on his lower legs. Histopathology from punch biopsies revealed “a dense infiltrate of monomorphic, mitotically active lymphoid cells with infiltration between the deep dermal collagen and the adipocytes in subcutaneous fat,” the investigators wrote, noting that the infiltrative cells were blastoid and 70% expressed cyclin D1, supporting cutaneous involvement of his systemic MCL.

Treatment was switched to ibrutinib and selinexor via a clinical trial, which led to temporary improvement of leg lesions; when the lesions returned, biopsy was performed with the same histopathological result. Lenalidomide and rituximab were started, but without success, and disease spread to the central nervous system.

Another biopsy of the skin lesions again supported cutaneous MCL, with tumor cells rimming individual adipocytes.

Because of this atypical morphology, fluorescence in situ hybridization (FISH) was conducted, revealing t(11;14)(q13:32) positivity, thereby “confirming the diagnosis of cutaneous involvement by systemic MCL,” the investigators wrote.

Genomic sequencing revealed abnormalities of “ataxia-telangiectasia mutated, mechanistic target of rapamycin kinase (mTOR), BCL6 corepressor, and FAS-associated factor 1, as well as the expected mutation in IGH-CCND1, leading to cyclin D1 upregulation.”

Subsequent treatment was unsuccessful, and the patient died from his disease.

“The complex and central role that mTOR plays in adipose homeostasis may link our tumor to its preference to the adipose tissue, although further investigation is warranted regarding specific genomic alterations in lymphomas and the implications these mutations have in the involvement of tumor cells with cutaneous and adipose environments,” the investigators wrote.

The investigators did not report conflicts of interest.

SOURCE: Laggis C et al. 2019 Apr 8. doi:10.1111/cup.13471.

An atypical case of cutaneous mantle cell lymphoma (MCL) with histomorphological features mimicking subcutaneous panniculitis-like T-cell lymphoma (SPTCL) highlights a “potential pitfall,” according to investigators.

This unusual case stresses the importance of molecular cytogenetics and/or immunohistochemistry for panniculitis-type lymphomas, reported lead author Caroline Laggis, MD of the University of Utah, Salt Lake City, and colleagues.

“While morphologic features of SPTCL, specifically rimming of adipocytes by neoplastic lymphoid cells, have been documented in other types of lymphomas, this case is exceptional in that the morphologic features of SPTCL are showed in secondary cutaneous involvement by MCL,” the investigators wrote. Their report is in Journal of Cutaneous Pathology.

The patient was a 69-year-old man who presented with 2-year history of night sweats and fever of unknown origin, and, closer to presentation, weight loss and tender bumps under the skin of his pelvic region.

Subsequent computed tomography and excisional lymph node biopsy led to a diagnosis of MCL, with a Mantle Cell Lymphoma International Prognostic Index of 5, suggesting aggressive, intermediate-risk disease. Further imaging showed involvement of the nasopharynx, and cervical and mediastinal lymph nodes.

Bendamustine and rituximab chemotherapy was given unremarkably until the final cycle, at which point the patient presented with tender subcutaneous nodules on his lower legs. Histopathology from punch biopsies revealed “a dense infiltrate of monomorphic, mitotically active lymphoid cells with infiltration between the deep dermal collagen and the adipocytes in subcutaneous fat,” the investigators wrote, noting that the infiltrative cells were blastoid and 70% expressed cyclin D1, supporting cutaneous involvement of his systemic MCL.

Treatment was switched to ibrutinib and selinexor via a clinical trial, which led to temporary improvement of leg lesions; when the lesions returned, biopsy was performed with the same histopathological result. Lenalidomide and rituximab were started, but without success, and disease spread to the central nervous system.

Another biopsy of the skin lesions again supported cutaneous MCL, with tumor cells rimming individual adipocytes.

Because of this atypical morphology, fluorescence in situ hybridization (FISH) was conducted, revealing t(11;14)(q13:32) positivity, thereby “confirming the diagnosis of cutaneous involvement by systemic MCL,” the investigators wrote.

Genomic sequencing revealed abnormalities of “ataxia-telangiectasia mutated, mechanistic target of rapamycin kinase (mTOR), BCL6 corepressor, and FAS-associated factor 1, as well as the expected mutation in IGH-CCND1, leading to cyclin D1 upregulation.”

Subsequent treatment was unsuccessful, and the patient died from his disease.

“The complex and central role that mTOR plays in adipose homeostasis may link our tumor to its preference to the adipose tissue, although further investigation is warranted regarding specific genomic alterations in lymphomas and the implications these mutations have in the involvement of tumor cells with cutaneous and adipose environments,” the investigators wrote.

The investigators did not report conflicts of interest.

SOURCE: Laggis C et al. 2019 Apr 8. doi:10.1111/cup.13471.

An atypical case of cutaneous mantle cell lymphoma (MCL) with histomorphological features mimicking subcutaneous panniculitis-like T-cell lymphoma (SPTCL) highlights a “potential pitfall,” according to investigators.

This unusual case stresses the importance of molecular cytogenetics and/or immunohistochemistry for panniculitis-type lymphomas, reported lead author Caroline Laggis, MD of the University of Utah, Salt Lake City, and colleagues.

“While morphologic features of SPTCL, specifically rimming of adipocytes by neoplastic lymphoid cells, have been documented in other types of lymphomas, this case is exceptional in that the morphologic features of SPTCL are showed in secondary cutaneous involvement by MCL,” the investigators wrote. Their report is in Journal of Cutaneous Pathology.

The patient was a 69-year-old man who presented with 2-year history of night sweats and fever of unknown origin, and, closer to presentation, weight loss and tender bumps under the skin of his pelvic region.

Subsequent computed tomography and excisional lymph node biopsy led to a diagnosis of MCL, with a Mantle Cell Lymphoma International Prognostic Index of 5, suggesting aggressive, intermediate-risk disease. Further imaging showed involvement of the nasopharynx, and cervical and mediastinal lymph nodes.

Bendamustine and rituximab chemotherapy was given unremarkably until the final cycle, at which point the patient presented with tender subcutaneous nodules on his lower legs. Histopathology from punch biopsies revealed “a dense infiltrate of monomorphic, mitotically active lymphoid cells with infiltration between the deep dermal collagen and the adipocytes in subcutaneous fat,” the investigators wrote, noting that the infiltrative cells were blastoid and 70% expressed cyclin D1, supporting cutaneous involvement of his systemic MCL.

Treatment was switched to ibrutinib and selinexor via a clinical trial, which led to temporary improvement of leg lesions; when the lesions returned, biopsy was performed with the same histopathological result. Lenalidomide and rituximab were started, but without success, and disease spread to the central nervous system.

Another biopsy of the skin lesions again supported cutaneous MCL, with tumor cells rimming individual adipocytes.

Because of this atypical morphology, fluorescence in situ hybridization (FISH) was conducted, revealing t(11;14)(q13:32) positivity, thereby “confirming the diagnosis of cutaneous involvement by systemic MCL,” the investigators wrote.

Genomic sequencing revealed abnormalities of “ataxia-telangiectasia mutated, mechanistic target of rapamycin kinase (mTOR), BCL6 corepressor, and FAS-associated factor 1, as well as the expected mutation in IGH-CCND1, leading to cyclin D1 upregulation.”

Subsequent treatment was unsuccessful, and the patient died from his disease.

“The complex and central role that mTOR plays in adipose homeostasis may link our tumor to its preference to the adipose tissue, although further investigation is warranted regarding specific genomic alterations in lymphomas and the implications these mutations have in the involvement of tumor cells with cutaneous and adipose environments,” the investigators wrote.

The investigators did not report conflicts of interest.

SOURCE: Laggis C et al. 2019 Apr 8. doi:10.1111/cup.13471.

Investigators have identified a mechanism of ibrutinib resistance in mantle cell lymphoma (MCL) and showed that a small molecule can overcome that resistance in vitro and in vivo.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

The team found that ibrutinib-resistant MCL cells rely on oxidative phosphorylation (OXPHOS) and glutaminolysis to survive.

Targeting the OXPHOS pathway with a small molecule, IACS-010759, inhibited the proliferation of ibrutinib-resistant cells in vitro.

IACS-010759 also decreased tumor volume and improved survival in mouse models of ibrutinib-resistant MCL and double-hit B-cell lymphoma.

Now, IACS-10759 is being tested in phase 1 trials of lymphoma and solid tumors (NCT03291938) as well as acute myeloid leukemia (NCT02882321).

Liang Zhang, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues conducted the preclinical research and described their findings in Science Translational Medicine.

The investigators sequenced samples from MCL patients with ibrutinib-sensitive and -resistant disease and found that “glutamine-fueled OXPHOS appears to be a prominent energy metabolism pathway in ibrutinib-resistant MCL cells.”

This finding prompted the team to test IACS-010759, an inhibitor of ETC complex I, in ibrutinib-resistant MCL. They theorized that the inhibitor would be effective because, during OXPHOS, electrons are transferred from electron donors to acceptors through the ETC in redox reactions that release energy to form ATP, and OXPHOS generates ATP to meet requirements for cell growth.

In experiments, IACS-010759 inhibited the proliferation of two ibrutinib-resistant MCL cell lines, Z-138 and Maver-1, in a dose-dependent manner.

The investigators also tested IACS-010759 in two mouse models of ibrutinib-resistant MCL. In both models, mice treated with IACS-010759 had a significant reduction in tumor volume, compared with controls. In one model, IACS-010759 extended survival by a median of 11 days.

Finally, the team tested IACS-010759 in a model of ibrutinib-resistant, double-hit (MYC and BCL-2) B-cell lymphoma with central nervous system involvement. Again, IACS-010759 significantly inhibited tumor growth. Compared to ibrutinib and vehicle control, IACS-010759 provided a median survival benefit of more than 20 days.

There were no toxicities associated with IACS-010759 treatment, according to the investigators.

This research was supported by the MD Anderson B Cell Lymphoma Moon Shot Project, Gary Rogers Foundation, Kinder Foundation, Cullen Foundation, Cancer Prevention Research Institute of Texas, and the National Institutes of Health. Most investigators reported having no competing interests, but two reported a patent (WO/2015/130790).

[email protected]

SOURCE: Zhang L et al. Sci Transl Med. 2019 May 8. doi: 10.1126/scitranslmed.aau1167.

Investigators have identified a mechanism of ibrutinib resistance in mantle cell lymphoma (MCL) and showed that a small molecule can overcome that resistance in vitro and in vivo.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

The team found that ibrutinib-resistant MCL cells rely on oxidative phosphorylation (OXPHOS) and glutaminolysis to survive.

Targeting the OXPHOS pathway with a small molecule, IACS-010759, inhibited the proliferation of ibrutinib-resistant cells in vitro.

IACS-010759 also decreased tumor volume and improved survival in mouse models of ibrutinib-resistant MCL and double-hit B-cell lymphoma.

Now, IACS-10759 is being tested in phase 1 trials of lymphoma and solid tumors (NCT03291938) as well as acute myeloid leukemia (NCT02882321).

Liang Zhang, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues conducted the preclinical research and described their findings in Science Translational Medicine.

The investigators sequenced samples from MCL patients with ibrutinib-sensitive and -resistant disease and found that “glutamine-fueled OXPHOS appears to be a prominent energy metabolism pathway in ibrutinib-resistant MCL cells.”

This finding prompted the team to test IACS-010759, an inhibitor of ETC complex I, in ibrutinib-resistant MCL. They theorized that the inhibitor would be effective because, during OXPHOS, electrons are transferred from electron donors to acceptors through the ETC in redox reactions that release energy to form ATP, and OXPHOS generates ATP to meet requirements for cell growth.

In experiments, IACS-010759 inhibited the proliferation of two ibrutinib-resistant MCL cell lines, Z-138 and Maver-1, in a dose-dependent manner.

The investigators also tested IACS-010759 in two mouse models of ibrutinib-resistant MCL. In both models, mice treated with IACS-010759 had a significant reduction in tumor volume, compared with controls. In one model, IACS-010759 extended survival by a median of 11 days.

Finally, the team tested IACS-010759 in a model of ibrutinib-resistant, double-hit (MYC and BCL-2) B-cell lymphoma with central nervous system involvement. Again, IACS-010759 significantly inhibited tumor growth. Compared to ibrutinib and vehicle control, IACS-010759 provided a median survival benefit of more than 20 days.

There were no toxicities associated with IACS-010759 treatment, according to the investigators.

This research was supported by the MD Anderson B Cell Lymphoma Moon Shot Project, Gary Rogers Foundation, Kinder Foundation, Cullen Foundation, Cancer Prevention Research Institute of Texas, and the National Institutes of Health. Most investigators reported having no competing interests, but two reported a patent (WO/2015/130790).

[email protected]

SOURCE: Zhang L et al. Sci Transl Med. 2019 May 8. doi: 10.1126/scitranslmed.aau1167.

Investigators have identified a mechanism of ibrutinib resistance in mantle cell lymphoma (MCL) and showed that a small molecule can overcome that resistance in vitro and in vivo.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

The team found that ibrutinib-resistant MCL cells rely on oxidative phosphorylation (OXPHOS) and glutaminolysis to survive.

Targeting the OXPHOS pathway with a small molecule, IACS-010759, inhibited the proliferation of ibrutinib-resistant cells in vitro.

IACS-010759 also decreased tumor volume and improved survival in mouse models of ibrutinib-resistant MCL and double-hit B-cell lymphoma.

Now, IACS-10759 is being tested in phase 1 trials of lymphoma and solid tumors (NCT03291938) as well as acute myeloid leukemia (NCT02882321).

Liang Zhang, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues conducted the preclinical research and described their findings in Science Translational Medicine.

The investigators sequenced samples from MCL patients with ibrutinib-sensitive and -resistant disease and found that “glutamine-fueled OXPHOS appears to be a prominent energy metabolism pathway in ibrutinib-resistant MCL cells.”

This finding prompted the team to test IACS-010759, an inhibitor of ETC complex I, in ibrutinib-resistant MCL. They theorized that the inhibitor would be effective because, during OXPHOS, electrons are transferred from electron donors to acceptors through the ETC in redox reactions that release energy to form ATP, and OXPHOS generates ATP to meet requirements for cell growth.

In experiments, IACS-010759 inhibited the proliferation of two ibrutinib-resistant MCL cell lines, Z-138 and Maver-1, in a dose-dependent manner.

The investigators also tested IACS-010759 in two mouse models of ibrutinib-resistant MCL. In both models, mice treated with IACS-010759 had a significant reduction in tumor volume, compared with controls. In one model, IACS-010759 extended survival by a median of 11 days.

Finally, the team tested IACS-010759 in a model of ibrutinib-resistant, double-hit (MYC and BCL-2) B-cell lymphoma with central nervous system involvement. Again, IACS-010759 significantly inhibited tumor growth. Compared to ibrutinib and vehicle control, IACS-010759 provided a median survival benefit of more than 20 days.

There were no toxicities associated with IACS-010759 treatment, according to the investigators.

This research was supported by the MD Anderson B Cell Lymphoma Moon Shot Project, Gary Rogers Foundation, Kinder Foundation, Cullen Foundation, Cancer Prevention Research Institute of Texas, and the National Institutes of Health. Most investigators reported having no competing interests, but two reported a patent (WO/2015/130790).

[email protected]

SOURCE: Zhang L et al. Sci Transl Med. 2019 May 8. doi: 10.1126/scitranslmed.aau1167.