B Cell Lymphoma

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.

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.

Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.

During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.

This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.

Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.

During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.

After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.

With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.

However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.

“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.

Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.

SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.

Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.

During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.

This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.

Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.

During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.

After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.

With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.

However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.

“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.

Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.

SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL), long-term treatment with the phosphoinositol 3-kinase inhibitor idelalisib appears safe and effective, according to investigators.

Final results from a phase 3 trial confirmed survival advantages when idelalisib is used in combination with rituximab, reported lead author Jeff P. Sharman, MD, of Willamette Valley Cancer Institute and Research Center in Springfield, Ore., and colleagues.

During follow-up, which exceeded 5 years in some patients, no new idelalisib-related adverse events were encountered, supporting the safety of long-term use, the investigators noted. The report is in the Journal of Clinical Oncology.

This study was “pivotal” for treating elderly patients with relapsed CLL, the investigators wrote, as these patients previously had few treatment options beyond supportive or palliative care.

Earlier results from the study showed that adding idelalisib to rituximab raised overall response rates from about 15.5% to 83.6% and median progression-free survival from 6.5 months to 19.4 months, resulting in “significantly better clinical outcomes compared with those seen with rituximab alone,” leading to approval by the Food and Drug Administration.

During the primary study, 110 patients received a combination of idelalisib and rituximab, while 108 patients received rituximab and placebo. The median patient age was 71 years, with a median of three lines of prior therapy. The present analysis focused on the 110 patients in the combination group who received at least one dose of idelalisib, whether or not they elected to participate in the extension phase.

After a median follow-up of 18 months, ranging from 0.3 months to 67.6 months, the overall response rate was 85.5% and the median progression-free survival was 20.3 months, both of which are similar to earlier findings. Median overall survival was 40.6 months.

With a median duration of exposure of 16.2 months, the safety analysis revealed no new idelalisib-related adverse events.

However, the investigators pointed out that prolonged therapy often led to diarrhea, which ultimately occurred in about half of patients (46.4%). Roughly equal amounts of patients experienced grade 2 (17.3%) or grade 3 or greater diarrhea (16.4%). In cases of grade 3 or greater diarrhea, steroid therapy was recommended, typically resulting in symptom resolution within 2 weeks; however, “there were insufficient numbers of patients to determine if steroid therapy affected the duration of symptoms,” the investigators wrote.

“The longer-term data presented here confirm the previously reported efficacy of targeting PI3K with idelalisib in patients with relapsed/refractory CLL and support the use of [idelalisib and rituximab] in this patient population with careful management of potential [adverse events],” they wrote.

Gilead Sciences funded the study. Dr. Sharman reported financial relationships with Gilead and other companies.

SOURCE: Sharman JP et al. J Clin Oncol. 2019 Apr 17. doi: 10.1200/JCO.18.01460.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – one offers potential in previously-treated cervical cancer patients with poor prognosis and the other confirms the role of R-CHOP as the standard of care in diffuse large B-cell lymphoma.

Pembrolizumab in KEYNOTE-158

In an international phase 2 “basket trial,” Hyun Cheol Chung, MD, PhD, and colleagues used pembrolizumab 200 mg every 3 weeks in 98 previously treated patients with advanced cervical cancer. Almost 84% of o the patients had PD-L1 positive tumors (greater than 1%). The authors said that viral induction of malignancy leads to antigen production and upregulation of PD-1. Therefore, advanced cervical cancer patients would likely express PD-L1 on tumor cells and respond to immune checkpoint inhibitor therapy.

In this interim report, there were 12 responses (all in PD-L1 positive patients), with three complete responses. Median response duration had not been reached at median follow-up of 10.2 months. Seven of 12 responses were ongoing at 12 months. There were grade 3-4 adverse events in 12.2% of patients and no treatment-related deaths.

The study – “Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study” – was published in the Journal of Clinical Oncology (2019 April 3. doi: 10.1200/JCO.18.01265).


The encouraging results of pembrolizumab in this generally chemotherapy-refractory patient population were consistent with other small, early-phase studies investigating immune checkpoint inhibitors that led to the accelerated approval of pembrolizumab in previously treated PD-L1 advanced cervical cancer patients with progressive disease after chemotherapy.
 

What this means in practice

Although excitement should be tempered about an interim report of an organ-specific subset of a phase 2 international basket trial that was heavily populated by young PS 0-1 patients and generated an overall response rate of less than 15%, no conventional chemotherapy or biologic agent offers the potential of complete or prolonged response, and disease control rates of 30%.

Clinical trials should always be the first choice, but immune checkpoint inhibitors offer an attractive off-study option.

Among many single agents in National Comprehensive Cancer Network guidelines for recurrent advanced cervical cancer after first-line cisplatin-based chemotherapy, there is a reason why pembrolizumab is listed first. For patients with PD-L1 expressing tumors or MSI-H/dMMR tumors, I would use it.
 

Frontline therapy in DLBCL

In a large, randomized phase 3 trial, close to 500 stage III-IV patients with diffuse large B-cell lymphoma (DLBCL), including primary mediastinal B-cell lymphoma and intravascular large B-cell lymphoma, were assigned to receive either conventional R-CHOP chemotherapy or the more complex, more toxic DA-EPOCH-R regimen that appeared superior in single-institution studies and was feasible in multi-institutional phase 2 trials.

The study – “Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303” – was published in the Journal of Clinical Oncology (2019 Apr 2. doi: 10.1200/JCO.18.01994).

In the study, progression-free survival and overall survival were no different for R-CHOP and DA-EPOCH-R, but – predictably – DA-EPOCH-R was more toxic and had more treatment discontinuations.

R-CHOP had better outcomes than expected. This suggests that patient-selection bias (more favorable histology, fewer high-risk subsets who required urgent therapy) may have been at work.

Further study of DA-EPOCH-R in higher IPI patients or in patients selected because of more adverse molecular features (DE phenotype, MYC+, double hit) is warranted given the poor outcomes with R-CHOP in high-risk patients, intriguing results in single institution trials of DA-EPOCH-R, and the underrepresentation of high-risk patients in the current study.
 

What this means in practice

Whether by virtue of the types of patients enrolled or because it is the best regimen in all DLBCL patients, R-CHOP remains the standard of care outside of a clinical trial.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – one offers potential in previously-treated cervical cancer patients with poor prognosis and the other confirms the role of R-CHOP as the standard of care in diffuse large B-cell lymphoma.

Pembrolizumab in KEYNOTE-158

In an international phase 2 “basket trial,” Hyun Cheol Chung, MD, PhD, and colleagues used pembrolizumab 200 mg every 3 weeks in 98 previously treated patients with advanced cervical cancer. Almost 84% of o the patients had PD-L1 positive tumors (greater than 1%). The authors said that viral induction of malignancy leads to antigen production and upregulation of PD-1. Therefore, advanced cervical cancer patients would likely express PD-L1 on tumor cells and respond to immune checkpoint inhibitor therapy.

In this interim report, there were 12 responses (all in PD-L1 positive patients), with three complete responses. Median response duration had not been reached at median follow-up of 10.2 months. Seven of 12 responses were ongoing at 12 months. There were grade 3-4 adverse events in 12.2% of patients and no treatment-related deaths.

The study – “Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study” – was published in the Journal of Clinical Oncology (2019 April 3. doi: 10.1200/JCO.18.01265).


The encouraging results of pembrolizumab in this generally chemotherapy-refractory patient population were consistent with other small, early-phase studies investigating immune checkpoint inhibitors that led to the accelerated approval of pembrolizumab in previously treated PD-L1 advanced cervical cancer patients with progressive disease after chemotherapy.
 

What this means in practice

Although excitement should be tempered about an interim report of an organ-specific subset of a phase 2 international basket trial that was heavily populated by young PS 0-1 patients and generated an overall response rate of less than 15%, no conventional chemotherapy or biologic agent offers the potential of complete or prolonged response, and disease control rates of 30%.

Clinical trials should always be the first choice, but immune checkpoint inhibitors offer an attractive off-study option.

Among many single agents in National Comprehensive Cancer Network guidelines for recurrent advanced cervical cancer after first-line cisplatin-based chemotherapy, there is a reason why pembrolizumab is listed first. For patients with PD-L1 expressing tumors or MSI-H/dMMR tumors, I would use it.
 

Frontline therapy in DLBCL

In a large, randomized phase 3 trial, close to 500 stage III-IV patients with diffuse large B-cell lymphoma (DLBCL), including primary mediastinal B-cell lymphoma and intravascular large B-cell lymphoma, were assigned to receive either conventional R-CHOP chemotherapy or the more complex, more toxic DA-EPOCH-R regimen that appeared superior in single-institution studies and was feasible in multi-institutional phase 2 trials.

The study – “Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303” – was published in the Journal of Clinical Oncology (2019 Apr 2. doi: 10.1200/JCO.18.01994).

In the study, progression-free survival and overall survival were no different for R-CHOP and DA-EPOCH-R, but – predictably – DA-EPOCH-R was more toxic and had more treatment discontinuations.

R-CHOP had better outcomes than expected. This suggests that patient-selection bias (more favorable histology, fewer high-risk subsets who required urgent therapy) may have been at work.

Further study of DA-EPOCH-R in higher IPI patients or in patients selected because of more adverse molecular features (DE phenotype, MYC+, double hit) is warranted given the poor outcomes with R-CHOP in high-risk patients, intriguing results in single institution trials of DA-EPOCH-R, and the underrepresentation of high-risk patients in the current study.
 

What this means in practice

Whether by virtue of the types of patients enrolled or because it is the best regimen in all DLBCL patients, R-CHOP remains the standard of care outside of a clinical trial.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I will treat my next patient,” I take a look at two recent trials – one offers potential in previously-treated cervical cancer patients with poor prognosis and the other confirms the role of R-CHOP as the standard of care in diffuse large B-cell lymphoma.

Pembrolizumab in KEYNOTE-158

In an international phase 2 “basket trial,” Hyun Cheol Chung, MD, PhD, and colleagues used pembrolizumab 200 mg every 3 weeks in 98 previously treated patients with advanced cervical cancer. Almost 84% of o the patients had PD-L1 positive tumors (greater than 1%). The authors said that viral induction of malignancy leads to antigen production and upregulation of PD-1. Therefore, advanced cervical cancer patients would likely express PD-L1 on tumor cells and respond to immune checkpoint inhibitor therapy.

In this interim report, there were 12 responses (all in PD-L1 positive patients), with three complete responses. Median response duration had not been reached at median follow-up of 10.2 months. Seven of 12 responses were ongoing at 12 months. There were grade 3-4 adverse events in 12.2% of patients and no treatment-related deaths.

The study – “Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study” – was published in the Journal of Clinical Oncology (2019 April 3. doi: 10.1200/JCO.18.01265).


The encouraging results of pembrolizumab in this generally chemotherapy-refractory patient population were consistent with other small, early-phase studies investigating immune checkpoint inhibitors that led to the accelerated approval of pembrolizumab in previously treated PD-L1 advanced cervical cancer patients with progressive disease after chemotherapy.
 

What this means in practice

Although excitement should be tempered about an interim report of an organ-specific subset of a phase 2 international basket trial that was heavily populated by young PS 0-1 patients and generated an overall response rate of less than 15%, no conventional chemotherapy or biologic agent offers the potential of complete or prolonged response, and disease control rates of 30%.

Clinical trials should always be the first choice, but immune checkpoint inhibitors offer an attractive off-study option.

Among many single agents in National Comprehensive Cancer Network guidelines for recurrent advanced cervical cancer after first-line cisplatin-based chemotherapy, there is a reason why pembrolizumab is listed first. For patients with PD-L1 expressing tumors or MSI-H/dMMR tumors, I would use it.
 

Frontline therapy in DLBCL

In a large, randomized phase 3 trial, close to 500 stage III-IV patients with diffuse large B-cell lymphoma (DLBCL), including primary mediastinal B-cell lymphoma and intravascular large B-cell lymphoma, were assigned to receive either conventional R-CHOP chemotherapy or the more complex, more toxic DA-EPOCH-R regimen that appeared superior in single-institution studies and was feasible in multi-institutional phase 2 trials.

The study – “Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303” – was published in the Journal of Clinical Oncology (2019 Apr 2. doi: 10.1200/JCO.18.01994).

In the study, progression-free survival and overall survival were no different for R-CHOP and DA-EPOCH-R, but – predictably – DA-EPOCH-R was more toxic and had more treatment discontinuations.

R-CHOP had better outcomes than expected. This suggests that patient-selection bias (more favorable histology, fewer high-risk subsets who required urgent therapy) may have been at work.

Further study of DA-EPOCH-R in higher IPI patients or in patients selected because of more adverse molecular features (DE phenotype, MYC+, double hit) is warranted given the poor outcomes with R-CHOP in high-risk patients, intriguing results in single institution trials of DA-EPOCH-R, and the underrepresentation of high-risk patients in the current study.
 

What this means in practice

Whether by virtue of the types of patients enrolled or because it is the best regimen in all DLBCL patients, R-CHOP remains the standard of care outside of a clinical trial.

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers, and in expanding access to clinical trials to medically underserved populations.

GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.

Will Pass/MDedge News

For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.

Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.

Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.

Will Pass/MDedge News

“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”

This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.

The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.

The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.

The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.

The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.

Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).

Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.

A closer look at the data revealed some patterns, Dr. Poynton said.

“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.

Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.

Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.

Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”

He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.

“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”

Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.

GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.

Will Pass/MDedge News

For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.

Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.

Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.

Will Pass/MDedge News

“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”

This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.

The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.

The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.

The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.

The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.

Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).

Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.

A closer look at the data revealed some patterns, Dr. Poynton said.

“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.

Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.

Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.

Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”

He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.

“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”

Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.

GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.

Will Pass/MDedge News

For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.

Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.

Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.

Will Pass/MDedge News

“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”

This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.

The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.

The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.

The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.

The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.

Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).

Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.

A closer look at the data revealed some patterns, Dr. Poynton said.

“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.

Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.

Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.

Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”

He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.

“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”

Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.

GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.

As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.

“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”

Monitoring

Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.

“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”

Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.

“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”

At MD Anderson, these earlier interventions have decreased severity of adverse events.

“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.

Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.

“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”

Grading toxicity

In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.

“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”

She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.

To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.

“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.

With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.

“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”

Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.

Choosing therapy

When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.

“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”

According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.

“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.

Dr. Nastoupil concluded her presentation with an overview and look to the future.

“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”

Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”

Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.

GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.

As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.

“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”

Monitoring

Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.

“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”

Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.

“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”

At MD Anderson, these earlier interventions have decreased severity of adverse events.

“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.

Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.

“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”

Grading toxicity

In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.

“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”

She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.

To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.

“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.

With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.

“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”

Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.

Choosing therapy

When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.

“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”

According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.

“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.

Dr. Nastoupil concluded her presentation with an overview and look to the future.

“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”

Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”

Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.

GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.

As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.

“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”

Monitoring

Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.

“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”

Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.

“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”

At MD Anderson, these earlier interventions have decreased severity of adverse events.

“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.

Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.

“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”

Grading toxicity

In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.

“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”

She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.

To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.

“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.

With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.

“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”

Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.

Choosing therapy

When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.

“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”

According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.

“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.

Dr. Nastoupil concluded her presentation with an overview and look to the future.

“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”

Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”

Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.

For older, less fit patients with mantle cell lymphoma (MCL) who may not be able to withstand the rigors of autologous stem cell transplants (ASCT), induction chemotherapy followed by radioimmunotherapy (RIT) consolidation with ibritumomab tiuxetan (Zevalin) was associated with good response rates and promising progression-free and overall survival rates, according to results of a phase 2 prospective study.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

RIT consolidation improved the complete response rate following first-line therapy from 41% to 91%, reported Wojciech Jurczak, MD, PhD, from the department of hematology at the Uniwersytet Jagiellonski in Krakow, Poland, and colleagues.

In the patients who received RIT following first-line induction, median progression-free survival was 3.3 years, and median overall survival was 6.5 years.

“The achieved responses are durable. Although, several novel agents and targeted therapies alone or in combination are currently being studied and developed in both the upfront and relapsed settings, RIT constitutes a valid and underused option especially in the first-line setting,” they wrote in a study published in Leukemia & Lymphoma.

The investigators enrolled 46 patients with clinical stage III to IV MCL who were either ineligible for, or unwilling to undergo, ASCT. The cohort included 34 patients with newly diagnosed advanced MCL and 12 with chemo-sensitive MCL in first relapse.

Patients were assigned to induction with six cycles of chemotherapy, with or without rituximab. Patients then underwent consolidation with RIT if they had confirmed reductions of the maximal lymph node diameter below 3 cm, their longest spleen measurement was below 15 cm, and bone marrow infiltration was less than 20%.

The chemotherapy regimens included either CVP (cyclophosphamide, vincristine and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), FC (fludarabine and cyclophosphamide), or FCM (FC plus mitoxantrone). Additionally, 27 of the 46 patients received rituximab, which was not considered the standard of care in Poland when the study began in 2005 and was delivered based on availability.

Of the 34 patients who received first-line chemotherapy, 20 received FC or FCM (with or without rituximab), and 14 received CHOP or CVP (with or without rituximab). In this group, 14 patients (41%) had a complete response, and 20 (95%) had a partial response. Of the 12 patients treated after first relapse, two (17%) had a complete response and 10 (83%) had partial response after induction.

RIT consolidation was performed 3-5 weeks after the last chemotherapy cycle. Patients with cytopenias after chemotherapy could wait an additional 3 weeks, during which they would receive a bridging dose of rituximab at the standard 375 mg/m² dose. The patients received two doses of rituximab 250 mg/m² administered 7 days then 24 hours prior to intravenous injection of ⁹⁰Y-labeled ibritumomab tiuxetan. The radiation doses delivered were 0.4 mCi/kg for patients with normal platelet counts and 0.3 mCi/kg for those with platelet counts from 100,000 to 150,000 cells/mm³. The maximum dose was 32.0 mCi.

The longest follow-up was out to slightly more than 8 years.

For the patients who received RIT after first-line induction, the complete response rate was 91%, and the partial response rate was 9%, compared with 41% complete response and 59% partial response after induction. In this group, the median progression-free survival was 3.3 years, and the median overall survival was 6.5 years.

For the patients who received RIT consolidation after first relapse and second chemotherapy regimen, the complete response rate was 75% and the partial response rate was 25%, compared with 17% and 83% at the end of second induction therapy. In this group, the median progression-free survival was 1.8 years (P less than .05, compared with patients treated after first-line responses), and the median overall survival was 2.2 years (P less than .05).

At 8 years of follow-up, 30% of patients who received RIT consolidation following first-line therapy were alive.

Adverse events included cytopenias in the majority of patients (77%), which were grade 1 or 2 in severity in 43% and grade 3 or 4 in 34%. Grade 3 or 4 thrombocytopenia and leukopenia occurred more frequently in patients treated with fludarabine-based regimens, and the thrombocytopenias in these patients lasted longer and required more platelet transfusions than those in CHOP- or CVP-treated patients. Two patients who underwent RIT following FCM induction died from prolonged thrombocytopenia, resulting in hemorrhagic strokes.

Among all patients, 22 patients developed infections following RIT consolidation. Five patients, all of whom had received fludarabine, required hospitalization for the treatment of the infections. There were no infection-related deaths, however.

Five patients developed the myelodysplastic syndrome, with a median onset time of 26 months. Of these patients, four had received fludarabine, and one had undergone a prior ASCT.

The trial was sponsored by Schering AG. Dr. Jurczak reported speakers bureau participation and research funding from multiple companies, not including Schering AG.

SOURCE: Jurczak W et al. Leuk Lymphoma. 2019 Apr 9. doi: 10.1080/10428194.2019.1602261.

For older, less fit patients with mantle cell lymphoma (MCL) who may not be able to withstand the rigors of autologous stem cell transplants (ASCT), induction chemotherapy followed by radioimmunotherapy (RIT) consolidation with ibritumomab tiuxetan (Zevalin) was associated with good response rates and promising progression-free and overall survival rates, according to results of a phase 2 prospective study.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

RIT consolidation improved the complete response rate following first-line therapy from 41% to 91%, reported Wojciech Jurczak, MD, PhD, from the department of hematology at the Uniwersytet Jagiellonski in Krakow, Poland, and colleagues.

In the patients who received RIT following first-line induction, median progression-free survival was 3.3 years, and median overall survival was 6.5 years.

“The achieved responses are durable. Although, several novel agents and targeted therapies alone or in combination are currently being studied and developed in both the upfront and relapsed settings, RIT constitutes a valid and underused option especially in the first-line setting,” they wrote in a study published in Leukemia & Lymphoma.

The investigators enrolled 46 patients with clinical stage III to IV MCL who were either ineligible for, or unwilling to undergo, ASCT. The cohort included 34 patients with newly diagnosed advanced MCL and 12 with chemo-sensitive MCL in first relapse.

Patients were assigned to induction with six cycles of chemotherapy, with or without rituximab. Patients then underwent consolidation with RIT if they had confirmed reductions of the maximal lymph node diameter below 3 cm, their longest spleen measurement was below 15 cm, and bone marrow infiltration was less than 20%.

The chemotherapy regimens included either CVP (cyclophosphamide, vincristine and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), FC (fludarabine and cyclophosphamide), or FCM (FC plus mitoxantrone). Additionally, 27 of the 46 patients received rituximab, which was not considered the standard of care in Poland when the study began in 2005 and was delivered based on availability.

Of the 34 patients who received first-line chemotherapy, 20 received FC or FCM (with or without rituximab), and 14 received CHOP or CVP (with or without rituximab). In this group, 14 patients (41%) had a complete response, and 20 (95%) had a partial response. Of the 12 patients treated after first relapse, two (17%) had a complete response and 10 (83%) had partial response after induction.

RIT consolidation was performed 3-5 weeks after the last chemotherapy cycle. Patients with cytopenias after chemotherapy could wait an additional 3 weeks, during which they would receive a bridging dose of rituximab at the standard 375 mg/m² dose. The patients received two doses of rituximab 250 mg/m² administered 7 days then 24 hours prior to intravenous injection of ⁹⁰Y-labeled ibritumomab tiuxetan. The radiation doses delivered were 0.4 mCi/kg for patients with normal platelet counts and 0.3 mCi/kg for those with platelet counts from 100,000 to 150,000 cells/mm³. The maximum dose was 32.0 mCi.

The longest follow-up was out to slightly more than 8 years.

For the patients who received RIT after first-line induction, the complete response rate was 91%, and the partial response rate was 9%, compared with 41% complete response and 59% partial response after induction. In this group, the median progression-free survival was 3.3 years, and the median overall survival was 6.5 years.

For the patients who received RIT consolidation after first relapse and second chemotherapy regimen, the complete response rate was 75% and the partial response rate was 25%, compared with 17% and 83% at the end of second induction therapy. In this group, the median progression-free survival was 1.8 years (P less than .05, compared with patients treated after first-line responses), and the median overall survival was 2.2 years (P less than .05).

At 8 years of follow-up, 30% of patients who received RIT consolidation following first-line therapy were alive.

Adverse events included cytopenias in the majority of patients (77%), which were grade 1 or 2 in severity in 43% and grade 3 or 4 in 34%. Grade 3 or 4 thrombocytopenia and leukopenia occurred more frequently in patients treated with fludarabine-based regimens, and the thrombocytopenias in these patients lasted longer and required more platelet transfusions than those in CHOP- or CVP-treated patients. Two patients who underwent RIT following FCM induction died from prolonged thrombocytopenia, resulting in hemorrhagic strokes.

Among all patients, 22 patients developed infections following RIT consolidation. Five patients, all of whom had received fludarabine, required hospitalization for the treatment of the infections. There were no infection-related deaths, however.

Five patients developed the myelodysplastic syndrome, with a median onset time of 26 months. Of these patients, four had received fludarabine, and one had undergone a prior ASCT.

The trial was sponsored by Schering AG. Dr. Jurczak reported speakers bureau participation and research funding from multiple companies, not including Schering AG.

SOURCE: Jurczak W et al. Leuk Lymphoma. 2019 Apr 9. doi: 10.1080/10428194.2019.1602261.

For older, less fit patients with mantle cell lymphoma (MCL) who may not be able to withstand the rigors of autologous stem cell transplants (ASCT), induction chemotherapy followed by radioimmunotherapy (RIT) consolidation with ibritumomab tiuxetan (Zevalin) was associated with good response rates and promising progression-free and overall survival rates, according to results of a phase 2 prospective study.

Wikimedia Commons/TexasPathologistMSW/CC-ASA 4.0 International

RIT consolidation improved the complete response rate following first-line therapy from 41% to 91%, reported Wojciech Jurczak, MD, PhD, from the department of hematology at the Uniwersytet Jagiellonski in Krakow, Poland, and colleagues.

In the patients who received RIT following first-line induction, median progression-free survival was 3.3 years, and median overall survival was 6.5 years.

“The achieved responses are durable. Although, several novel agents and targeted therapies alone or in combination are currently being studied and developed in both the upfront and relapsed settings, RIT constitutes a valid and underused option especially in the first-line setting,” they wrote in a study published in Leukemia & Lymphoma.

The investigators enrolled 46 patients with clinical stage III to IV MCL who were either ineligible for, or unwilling to undergo, ASCT. The cohort included 34 patients with newly diagnosed advanced MCL and 12 with chemo-sensitive MCL in first relapse.

Patients were assigned to induction with six cycles of chemotherapy, with or without rituximab. Patients then underwent consolidation with RIT if they had confirmed reductions of the maximal lymph node diameter below 3 cm, their longest spleen measurement was below 15 cm, and bone marrow infiltration was less than 20%.

The chemotherapy regimens included either CVP (cyclophosphamide, vincristine and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), FC (fludarabine and cyclophosphamide), or FCM (FC plus mitoxantrone). Additionally, 27 of the 46 patients received rituximab, which was not considered the standard of care in Poland when the study began in 2005 and was delivered based on availability.

Of the 34 patients who received first-line chemotherapy, 20 received FC or FCM (with or without rituximab), and 14 received CHOP or CVP (with or without rituximab). In this group, 14 patients (41%) had a complete response, and 20 (95%) had a partial response. Of the 12 patients treated after first relapse, two (17%) had a complete response and 10 (83%) had partial response after induction.

RIT consolidation was performed 3-5 weeks after the last chemotherapy cycle. Patients with cytopenias after chemotherapy could wait an additional 3 weeks, during which they would receive a bridging dose of rituximab at the standard 375 mg/m² dose. The patients received two doses of rituximab 250 mg/m² administered 7 days then 24 hours prior to intravenous injection of ⁹⁰Y-labeled ibritumomab tiuxetan. The radiation doses delivered were 0.4 mCi/kg for patients with normal platelet counts and 0.3 mCi/kg for those with platelet counts from 100,000 to 150,000 cells/mm³. The maximum dose was 32.0 mCi.

The longest follow-up was out to slightly more than 8 years.

For the patients who received RIT after first-line induction, the complete response rate was 91%, and the partial response rate was 9%, compared with 41% complete response and 59% partial response after induction. In this group, the median progression-free survival was 3.3 years, and the median overall survival was 6.5 years.

For the patients who received RIT consolidation after first relapse and second chemotherapy regimen, the complete response rate was 75% and the partial response rate was 25%, compared with 17% and 83% at the end of second induction therapy. In this group, the median progression-free survival was 1.8 years (P less than .05, compared with patients treated after first-line responses), and the median overall survival was 2.2 years (P less than .05).

At 8 years of follow-up, 30% of patients who received RIT consolidation following first-line therapy were alive.

Adverse events included cytopenias in the majority of patients (77%), which were grade 1 or 2 in severity in 43% and grade 3 or 4 in 34%. Grade 3 or 4 thrombocytopenia and leukopenia occurred more frequently in patients treated with fludarabine-based regimens, and the thrombocytopenias in these patients lasted longer and required more platelet transfusions than those in CHOP- or CVP-treated patients. Two patients who underwent RIT following FCM induction died from prolonged thrombocytopenia, resulting in hemorrhagic strokes.

Among all patients, 22 patients developed infections following RIT consolidation. Five patients, all of whom had received fludarabine, required hospitalization for the treatment of the infections. There were no infection-related deaths, however.

Five patients developed the myelodysplastic syndrome, with a median onset time of 26 months. Of these patients, four had received fludarabine, and one had undergone a prior ASCT.

The trial was sponsored by Schering AG. Dr. Jurczak reported speakers bureau participation and research funding from multiple companies, not including Schering AG.

SOURCE: Jurczak W et al. Leuk Lymphoma. 2019 Apr 9. doi: 10.1080/10428194.2019.1602261.

A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.

Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.

The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.

In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).

All patients were prescribed 90 mg/m² bendamustine on days 1 and 2 combined with 375 mg/m² rituximab on day 0 of the first course, and 500 mg/m² rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.

The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.

A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.

Additionally, one patient developed sepsis during treatment and died after the first course of therapy.

“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.

The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.

More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.

The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
 

SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.

A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.

Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.

The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.

In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).

All patients were prescribed 90 mg/m² bendamustine on days 1 and 2 combined with 375 mg/m² rituximab on day 0 of the first course, and 500 mg/m² rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.

The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.

A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.

Additionally, one patient developed sepsis during treatment and died after the first course of therapy.

“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.

The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.

More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.

The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
 

SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.

A combination of bendamustine and rituximab generated an 88% overall response rate and 96% overall survival rate at 2 years among patients with chronic lymphocytic leukemia (CLL) in a study of 83 patients aged 53-83 years.

Although combined fludarabine, cyclophosphamide, and rituximab has demonstrated success in younger patients with CLL, this therapy is often considered too aggressive for the majority of CLL patients, who tend to be older and have multiple comorbidities, wrote Martin Špacek, MD, of Charles University and General University Hospital in Prague and his colleagues.

The alternative treatment combination of bendamustine and rituximab (BR) has not been well studied in patients with comorbidities, they said.

In a study published in Leukemia Research, the researchers enrolled 83 previously untreated adults with progressive CLL. The average age of the participants was 71 years, and 61% were men. The median creatinine clearance for the study population was 65 mL/min, and all patients had comorbidities, defined as scores greater than 6 on the Cumulative Illness Rating Scale (CIRS).

All patients were prescribed 90 mg/m² bendamustine on days 1 and 2 combined with 375 mg/m² rituximab on day 0 of the first course, and 500 mg/m² rituximab on day 1 during subsequent courses every 28 days for a maximum of six cycles.

The overall response rate to BR was 88.0%, with a complete response rate of 20.5%. At 2 years, progression-free survival and overall survival rates were 69.9% and 96.2%, respectively.

A total of 51 patients (61.4%) experienced at least one grade 3 or 4 adverse event. The most common hematologic effects were neutropenia (40 patients), thrombocytopenia (14 patients), and anemia (8 patients). The most common nonhematologic effects were grade 3– or grade 4–level infections in 12 patients. Six patients developed severe skin rash.

Additionally, one patient developed sepsis during treatment and died after the first course of therapy.

“Age and CIRS failed to predict any severe toxicities or BR dose reduction,” the researchers noted.

The findings support data from previous studies and represent the largest study of CLL patients with significant comorbidities to be treated with BR, the researchers said.

More prospective research is needed, but the results demonstrate that “chemoimmunotherapy with BR is an effective therapeutic option with manageable toxicity for the initial treatment of CLL patients with significant comorbidities,” the investigators wrote.

The study was supported by the Ministry of Health, Czech Republic, the Charles University Progres program, and the Czech CLL Study Group. Researchers reported honoraria and travel grants from Mundipharma and Roche.
 

SOURCE: Spacek M et al. Leuk Res. 2019;79:17-21.

A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.

The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).

ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.

In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.

“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”

Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
 

Preclinical results

Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.

Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.

However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.

The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
 

Clinical results

Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.

The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).

“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.

At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.

ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.

This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.

[email protected]

SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.

A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.

The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).

ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.

In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.

“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”

Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
 

Preclinical results

Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.

Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.

However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.

The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
 

Clinical results

Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.

The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).

“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.

At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.

ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.

This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.

[email protected]

SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.

A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.

The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).

ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.

In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.

“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”

Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
 

Preclinical results

Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.

Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.

However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.

The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
 

Clinical results

Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.

The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).

“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.

At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.

ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.

This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.

[email protected]

SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.

The use of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) as upfront treatment in patients with diffuse large B-cell lymphoma (DLBCL) showed greater toxicity and did not improve progression-free survival versus standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), according to results from a phase 3 trial.

Nephron/Wikimedia Commons/CC BY-SA 3.0

“Less favorable outcomes for patients with recurrent DLBCL prompted efforts to improve first-line approaches and biomarkers to identify high-risk patients,” wrote Nancy L. Bartlett, MD, of Washington University, St. Louis, and her colleagues wrote in the Journal of Clinical Oncology.

The Alliance/CALGB 50303 study included 491 patients with DLBCL who were randomized in a 1:1 fashion to receive DA-EPOCH-R or R-CHOP every 21 days for a total of six cycles. Dosing for the DA-EPOCH-R regimen was determined using absolute neutrophil and platelet counts.

The primary endpoint measured was progression-free survival (PFS); secondary endpoints included safety, overall survival (OS), and response rate.

After a median follow-up of 5.2 years, the researchers found no significant difference in PFS between the study arms (DA-EPOCH-R hazard ratio, 0.93; 95% confidence interval, 0.68-1.27; P = .65). Additionally, there was no significant difference in OS (HR, 1.09; 95% CI, 0.75-1.59; P = .64).

The overall response rate was 88.0% in the R-CHOP arm versus 86.7% in the DA-EPOCH-R arm (P = .67).

With respect to safety, grade 3 or 4 adverse events were more frequently seen in the DA-EPOCH-R group than in the R-CHOP group (P less than .001). These toxicities included febrile neutropenia, infections, neuropathy, and mucositis.

The researchers did see significantly improved PFS in the DA-EPOCH-R arm in post hoc subset analyses of patients with International Prognostic Index (IPI) 3-5, but the subset analysis “was unplanned and not powered” and the significance “must be tempered in light of multiple comparisons.”

“We now understand DLBCL is even more heterogeneous than appreciated when this trial was designed,” the researchers wrote. “Therefore, the National Clinical Trials Network is planning a precision medicine approach to identify molecular subsets of DLBCL and determine if specific chemotherapy platforms and/or targeted agents offer differential benefit.”

The study was supported by the National Cancer Institute. The authors reported financial relationships with Bristol-Myers Squibb, Celgene, Janssen, Jazz Pharmaceuticals, Morphosys, and other companies.

SOURCE: Bartlett NL et al. J Clin Oncol. 2019 Apr 2. doi: 10.1200/JCO.18.01994.

The use of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) as upfront treatment in patients with diffuse large B-cell lymphoma (DLBCL) showed greater toxicity and did not improve progression-free survival versus standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), according to results from a phase 3 trial.

Nephron/Wikimedia Commons/CC BY-SA 3.0

“Less favorable outcomes for patients with recurrent DLBCL prompted efforts to improve first-line approaches and biomarkers to identify high-risk patients,” wrote Nancy L. Bartlett, MD, of Washington University, St. Louis, and her colleagues wrote in the Journal of Clinical Oncology.

The Alliance/CALGB 50303 study included 491 patients with DLBCL who were randomized in a 1:1 fashion to receive DA-EPOCH-R or R-CHOP every 21 days for a total of six cycles. Dosing for the DA-EPOCH-R regimen was determined using absolute neutrophil and platelet counts.

The primary endpoint measured was progression-free survival (PFS); secondary endpoints included safety, overall survival (OS), and response rate.

After a median follow-up of 5.2 years, the researchers found no significant difference in PFS between the study arms (DA-EPOCH-R hazard ratio, 0.93; 95% confidence interval, 0.68-1.27; P = .65). Additionally, there was no significant difference in OS (HR, 1.09; 95% CI, 0.75-1.59; P = .64).

The overall response rate was 88.0% in the R-CHOP arm versus 86.7% in the DA-EPOCH-R arm (P = .67).

With respect to safety, grade 3 or 4 adverse events were more frequently seen in the DA-EPOCH-R group than in the R-CHOP group (P less than .001). These toxicities included febrile neutropenia, infections, neuropathy, and mucositis.

The researchers did see significantly improved PFS in the DA-EPOCH-R arm in post hoc subset analyses of patients with International Prognostic Index (IPI) 3-5, but the subset analysis “was unplanned and not powered” and the significance “must be tempered in light of multiple comparisons.”

“We now understand DLBCL is even more heterogeneous than appreciated when this trial was designed,” the researchers wrote. “Therefore, the National Clinical Trials Network is planning a precision medicine approach to identify molecular subsets of DLBCL and determine if specific chemotherapy platforms and/or targeted agents offer differential benefit.”

The study was supported by the National Cancer Institute. The authors reported financial relationships with Bristol-Myers Squibb, Celgene, Janssen, Jazz Pharmaceuticals, Morphosys, and other companies.

SOURCE: Bartlett NL et al. J Clin Oncol. 2019 Apr 2. doi: 10.1200/JCO.18.01994.

The use of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) as upfront treatment in patients with diffuse large B-cell lymphoma (DLBCL) showed greater toxicity and did not improve progression-free survival versus standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), according to results from a phase 3 trial.

Nephron/Wikimedia Commons/CC BY-SA 3.0

“Less favorable outcomes for patients with recurrent DLBCL prompted efforts to improve first-line approaches and biomarkers to identify high-risk patients,” wrote Nancy L. Bartlett, MD, of Washington University, St. Louis, and her colleagues wrote in the Journal of Clinical Oncology.

The Alliance/CALGB 50303 study included 491 patients with DLBCL who were randomized in a 1:1 fashion to receive DA-EPOCH-R or R-CHOP every 21 days for a total of six cycles. Dosing for the DA-EPOCH-R regimen was determined using absolute neutrophil and platelet counts.

The primary endpoint measured was progression-free survival (PFS); secondary endpoints included safety, overall survival (OS), and response rate.

After a median follow-up of 5.2 years, the researchers found no significant difference in PFS between the study arms (DA-EPOCH-R hazard ratio, 0.93; 95% confidence interval, 0.68-1.27; P = .65). Additionally, there was no significant difference in OS (HR, 1.09; 95% CI, 0.75-1.59; P = .64).

The overall response rate was 88.0% in the R-CHOP arm versus 86.7% in the DA-EPOCH-R arm (P = .67).

With respect to safety, grade 3 or 4 adverse events were more frequently seen in the DA-EPOCH-R group than in the R-CHOP group (P less than .001). These toxicities included febrile neutropenia, infections, neuropathy, and mucositis.

The researchers did see significantly improved PFS in the DA-EPOCH-R arm in post hoc subset analyses of patients with International Prognostic Index (IPI) 3-5, but the subset analysis “was unplanned and not powered” and the significance “must be tempered in light of multiple comparisons.”

“We now understand DLBCL is even more heterogeneous than appreciated when this trial was designed,” the researchers wrote. “Therefore, the National Clinical Trials Network is planning a precision medicine approach to identify molecular subsets of DLBCL and determine if specific chemotherapy platforms and/or targeted agents offer differential benefit.”

The study was supported by the National Cancer Institute. The authors reported financial relationships with Bristol-Myers Squibb, Celgene, Janssen, Jazz Pharmaceuticals, Morphosys, and other companies.

SOURCE: Bartlett NL et al. J Clin Oncol. 2019 Apr 2. doi: 10.1200/JCO.18.01994.

Favorable results from a phase 2 trial have prompted further development of polatuzumab vedotin in non-Hodgkin lymphoma.

In the ROMULUS trial, polatuzumab vedotin plus rituximab (R-pola) produced more durable responses than did pinatuzumab vedotin plus rituximab (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL).

Researchers also observed a more favorable benefit-risk profile with R-pola.

Franck Morschhauser, MD, of Centre Hospitalier Régional Universitaire de Lille, France, and his colleagues described these findings in the Lancet Haematology.

The ROMULUS trial included 81 DLBCL patients and 42 FL patients. They were randomized to receive R-pola or R-pina (rituximab at 375 mg/m² plus either antibody-drug conjugate at 2.4 mg/kg) every 21 days until disease progression or unacceptable toxicity for up to 1 year.

Among DLBCL patients, the median age was 69 years in the R-pina arm and 68 years in the R-pola arm. Among FL patients, the median age was 59 years in the R-pina arm and 67 years in the R-pola arm.

Seventy-six percent of DLBCL patients randomized to R-pina were refractory to their last treatment, as were 80% of DLBCL patients assigned to R-pola, 52% of FL patients assigned to R-pina, and 35% of FL patients assigned to R-pola.

The median number of prior systemic therapies was three in the R-pina DLBCL arm, the R-pola DLBCL arm, and the R-pina FL arm. The median number of prior therapies was two in the R-pola FL arm.

Response and survival

Among the DLBCL patients, R-pina produced an objective response rate (ORR) of 60% and a complete response (CR) rate of 26%. R-pola produced an ORR of 54% and a CR rate of 21%. The median duration of response was 6.2 months in the R-pina arm and 13.4 months in the R-pola arm.

The median progression-free survival in the DLBCL cohort was 5.4 months for the R-pina arm and 5.6 months for the R-pola arm. The median overall survival was 16.5 months and 20.1 months, respectively.

In the FL cohort, R-pina produced an ORR of 62% and a CR rate of 5%. R-pola produced an ORR of 70% and a CR rate of 45%. The median duration of response was 6.5 months in the R-pina arm and 9.4 months in the R-pola arm.

The median progression-free survival in the FL cohort was 12.7 months for the R-pina arm and 15.3 months for the R-pola arm. The 2-year overall survival rate was 90.5% and 87.8%, respectively. The median overall survival was not reached in either arm.

“Patients treated with R-pola tended to have longer durations of response than those receiving R-pina (particularly those with relapsed or refractory diffuse large B-cell lymphoma), and the results for R-pola compared favorably with other novel antilymphoma agents,” Dr. Morschhauser and his colleagues wrote.

Safety

Among DLBCL patients, serious adverse events (AEs) occurred in 50.0% of those in the R-pina arm and 35.9% of those in the R-pola arm. Among FL patients, serious AEs occurred in 28.6% of those the R-pina arm and 35.0% of those in the R-pola arm.

Ten grade 5 AEs occurred in nine DLBCL patients who received R-pina (21.4%). These events included two cases of sepsis, influenza and pneumonia in the same patient, general physical health deterioration including one death attributed to disease progression, and one case each of Clostridium difficile sepsis, respiratory failure, urosepsis, and sudden death.

There was one grade 5 AE in a FL patient who received R-pola. The 84-year-old patient died of pulmonary congestion 64 days after the last of 12 cycles of treatment.

There were no fatal AEs in the other arms.

“These findings make pola a promising novel candidate for further clinical evaluation in combination regimens in treatment-refractory patients and also in a first-line setting in B-cell non-Hodgkin lymphoma,” Dr. Morschhauser and his colleagues wrote.

Polatuzumab vedotin was chosen by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response, compared with pinatuzumab vedotin.

Polatuzumab vedotin is currently under investigation in the phase 3 POLARIX study. The drug is being combined with rituximab, cyclophosphamide, doxorubicin, and prednisone and compared to rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL.

The ROMULUS study was funded by F Hoffmann-La Roche. The study authors reported relationships with Roche and other companies.

[email protected]

SOURCE: Morschhauser F et al. Lancet Haematol. 2019 Mar 29. doi: 10.1016/S2352-3026(19)30026-2.

Favorable results from a phase 2 trial have prompted further development of polatuzumab vedotin in non-Hodgkin lymphoma.

In the ROMULUS trial, polatuzumab vedotin plus rituximab (R-pola) produced more durable responses than did pinatuzumab vedotin plus rituximab (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL).

Researchers also observed a more favorable benefit-risk profile with R-pola.

Franck Morschhauser, MD, of Centre Hospitalier Régional Universitaire de Lille, France, and his colleagues described these findings in the Lancet Haematology.

The ROMULUS trial included 81 DLBCL patients and 42 FL patients. They were randomized to receive R-pola or R-pina (rituximab at 375 mg/m² plus either antibody-drug conjugate at 2.4 mg/kg) every 21 days until disease progression or unacceptable toxicity for up to 1 year.

Among DLBCL patients, the median age was 69 years in the R-pina arm and 68 years in the R-pola arm. Among FL patients, the median age was 59 years in the R-pina arm and 67 years in the R-pola arm.

Seventy-six percent of DLBCL patients randomized to R-pina were refractory to their last treatment, as were 80% of DLBCL patients assigned to R-pola, 52% of FL patients assigned to R-pina, and 35% of FL patients assigned to R-pola.

The median number of prior systemic therapies was three in the R-pina DLBCL arm, the R-pola DLBCL arm, and the R-pina FL arm. The median number of prior therapies was two in the R-pola FL arm.

Response and survival

Among the DLBCL patients, R-pina produced an objective response rate (ORR) of 60% and a complete response (CR) rate of 26%. R-pola produced an ORR of 54% and a CR rate of 21%. The median duration of response was 6.2 months in the R-pina arm and 13.4 months in the R-pola arm.

The median progression-free survival in the DLBCL cohort was 5.4 months for the R-pina arm and 5.6 months for the R-pola arm. The median overall survival was 16.5 months and 20.1 months, respectively.

In the FL cohort, R-pina produced an ORR of 62% and a CR rate of 5%. R-pola produced an ORR of 70% and a CR rate of 45%. The median duration of response was 6.5 months in the R-pina arm and 9.4 months in the R-pola arm.

The median progression-free survival in the FL cohort was 12.7 months for the R-pina arm and 15.3 months for the R-pola arm. The 2-year overall survival rate was 90.5% and 87.8%, respectively. The median overall survival was not reached in either arm.

“Patients treated with R-pola tended to have longer durations of response than those receiving R-pina (particularly those with relapsed or refractory diffuse large B-cell lymphoma), and the results for R-pola compared favorably with other novel antilymphoma agents,” Dr. Morschhauser and his colleagues wrote.

Safety

Among DLBCL patients, serious adverse events (AEs) occurred in 50.0% of those in the R-pina arm and 35.9% of those in the R-pola arm. Among FL patients, serious AEs occurred in 28.6% of those the R-pina arm and 35.0% of those in the R-pola arm.

Ten grade 5 AEs occurred in nine DLBCL patients who received R-pina (21.4%). These events included two cases of sepsis, influenza and pneumonia in the same patient, general physical health deterioration including one death attributed to disease progression, and one case each of Clostridium difficile sepsis, respiratory failure, urosepsis, and sudden death.

There was one grade 5 AE in a FL patient who received R-pola. The 84-year-old patient died of pulmonary congestion 64 days after the last of 12 cycles of treatment.

There were no fatal AEs in the other arms.

“These findings make pola a promising novel candidate for further clinical evaluation in combination regimens in treatment-refractory patients and also in a first-line setting in B-cell non-Hodgkin lymphoma,” Dr. Morschhauser and his colleagues wrote.

Polatuzumab vedotin was chosen by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response, compared with pinatuzumab vedotin.

Polatuzumab vedotin is currently under investigation in the phase 3 POLARIX study. The drug is being combined with rituximab, cyclophosphamide, doxorubicin, and prednisone and compared to rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL.

The ROMULUS study was funded by F Hoffmann-La Roche. The study authors reported relationships with Roche and other companies.

[email protected]

SOURCE: Morschhauser F et al. Lancet Haematol. 2019 Mar 29. doi: 10.1016/S2352-3026(19)30026-2.

Favorable results from a phase 2 trial have prompted further development of polatuzumab vedotin in non-Hodgkin lymphoma.

In the ROMULUS trial, polatuzumab vedotin plus rituximab (R-pola) produced more durable responses than did pinatuzumab vedotin plus rituximab (R-pina) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL).

Researchers also observed a more favorable benefit-risk profile with R-pola.

Franck Morschhauser, MD, of Centre Hospitalier Régional Universitaire de Lille, France, and his colleagues described these findings in the Lancet Haematology.

The ROMULUS trial included 81 DLBCL patients and 42 FL patients. They were randomized to receive R-pola or R-pina (rituximab at 375 mg/m² plus either antibody-drug conjugate at 2.4 mg/kg) every 21 days until disease progression or unacceptable toxicity for up to 1 year.

Among DLBCL patients, the median age was 69 years in the R-pina arm and 68 years in the R-pola arm. Among FL patients, the median age was 59 years in the R-pina arm and 67 years in the R-pola arm.

Seventy-six percent of DLBCL patients randomized to R-pina were refractory to their last treatment, as were 80% of DLBCL patients assigned to R-pola, 52% of FL patients assigned to R-pina, and 35% of FL patients assigned to R-pola.

The median number of prior systemic therapies was three in the R-pina DLBCL arm, the R-pola DLBCL arm, and the R-pina FL arm. The median number of prior therapies was two in the R-pola FL arm.

Response and survival

Among the DLBCL patients, R-pina produced an objective response rate (ORR) of 60% and a complete response (CR) rate of 26%. R-pola produced an ORR of 54% and a CR rate of 21%. The median duration of response was 6.2 months in the R-pina arm and 13.4 months in the R-pola arm.

The median progression-free survival in the DLBCL cohort was 5.4 months for the R-pina arm and 5.6 months for the R-pola arm. The median overall survival was 16.5 months and 20.1 months, respectively.

In the FL cohort, R-pina produced an ORR of 62% and a CR rate of 5%. R-pola produced an ORR of 70% and a CR rate of 45%. The median duration of response was 6.5 months in the R-pina arm and 9.4 months in the R-pola arm.

The median progression-free survival in the FL cohort was 12.7 months for the R-pina arm and 15.3 months for the R-pola arm. The 2-year overall survival rate was 90.5% and 87.8%, respectively. The median overall survival was not reached in either arm.

“Patients treated with R-pola tended to have longer durations of response than those receiving R-pina (particularly those with relapsed or refractory diffuse large B-cell lymphoma), and the results for R-pola compared favorably with other novel antilymphoma agents,” Dr. Morschhauser and his colleagues wrote.

Safety

Among DLBCL patients, serious adverse events (AEs) occurred in 50.0% of those in the R-pina arm and 35.9% of those in the R-pola arm. Among FL patients, serious AEs occurred in 28.6% of those the R-pina arm and 35.0% of those in the R-pola arm.

Ten grade 5 AEs occurred in nine DLBCL patients who received R-pina (21.4%). These events included two cases of sepsis, influenza and pneumonia in the same patient, general physical health deterioration including one death attributed to disease progression, and one case each of Clostridium difficile sepsis, respiratory failure, urosepsis, and sudden death.

There was one grade 5 AE in a FL patient who received R-pola. The 84-year-old patient died of pulmonary congestion 64 days after the last of 12 cycles of treatment.

There were no fatal AEs in the other arms.

“These findings make pola a promising novel candidate for further clinical evaluation in combination regimens in treatment-refractory patients and also in a first-line setting in B-cell non-Hodgkin lymphoma,” Dr. Morschhauser and his colleagues wrote.

Polatuzumab vedotin was chosen by the study funder for further development in non-Hodgkin lymphoma, partly because of longer durations of response, compared with pinatuzumab vedotin.

Polatuzumab vedotin is currently under investigation in the phase 3 POLARIX study. The drug is being combined with rituximab, cyclophosphamide, doxorubicin, and prednisone and compared to rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL.

The ROMULUS study was funded by F Hoffmann-La Roche. The study authors reported relationships with Roche and other companies.

[email protected]

SOURCE: Morschhauser F et al. Lancet Haematol. 2019 Mar 29. doi: 10.1016/S2352-3026(19)30026-2.