Follicular Lymphoma

A macrophage-activating immune checkpoint inhibitor, combined with rituximab therapy, was safe and produced durable complete responses in patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study.

Courtesy Stanford Medicine

Mainly low-grade toxic effects were seen on treatment with Hu5F9-G4 (5F9) and rituximab, which induced responses in more than half of patients, of which more than one-third were complete responses, the study investigators reported.

Most of the responses were ongoing at the time of data cutoff, suggesting durable responses with the combination of rituximab and 5F9 – a humanized monoclonal antibody that blocks CD47, an antiphagocytic or “do not eat me” signal overexpressed by most cancers, Ranjana Advani, MD, of Stanford (Calif.) University, and her coauthors wrote.

“The macrophage-mediated activity of 5F9 plus rituximab may serve as an effective new immunotherapy for stimulating the innate immune system,” Dr. Advani and her colleagues reported in the New England Journal of Medicine.

The study included 22 patients, including 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma, who had received a median of four prior therapies. Almost all of the non-Hodgkin lymphomas (21, or 95%) were refractory to rituximab.

All patients received intravenous 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10-30 mg/kg in three dose-escalation cohorts, given until disease progression or lack of clinical benefit. Intravenous rituximab at 375 mg/m² weekly was started on the second week of the first cycle, and then monthly for cycles 2 through 6.

“Substantial antitumor activity” was seen with this chemotherapy-free regimen in a group of heavily pretreated, largely rituximab-refractory patients, Dr. Advani and her coauthors wrote in their report.

The objective response rate was 50%, including a 36% complete response rate in the intent-to-treat analysis. For DLBCL, the rates of objective and complete responses were 40% and 33%, while for follicular lymphoma, they were 71% and 43%.

The median duration of response was not reached in either disease cohort with a median follow-up of 6.2 months for DLBCL and 8.1 months for follicular lymphoma. Of the 11 patients who responded, 10 (91%) were still in response at the time of data cutoff. “Longer follow-up is needed,” the investigators wrote.

Most adverse events were seen within the first few weeks of treatment and mainly included anemia and infusion-related reactions. The anemia was an expected, on-target effect of 5F9 because of selective clearance of older red cells, which was predictable, transient, and mitigated by the maintenance dosing strategy employed in this phase 1b trial.

“As red cells age, they lose CD47 expression and gain expression of prophagocytic signals, leading to homeostatic clearance,” they wrote.

The activity of 5F9 and rituximab is “synergistic” based on the results of previous, preclinical investigations in models of lymphoma, Dr. Advani and her coauthors added.

A phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell non-Hodgkin lymphoma is ongoing, according to their report.

The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.

SOURCE: Advani R et al. N Engl J Med. 2018;379:1711-21.

A macrophage-activating immune checkpoint inhibitor, combined with rituximab therapy, was safe and produced durable complete responses in patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study.

Courtesy Stanford Medicine

Mainly low-grade toxic effects were seen on treatment with Hu5F9-G4 (5F9) and rituximab, which induced responses in more than half of patients, of which more than one-third were complete responses, the study investigators reported.

Most of the responses were ongoing at the time of data cutoff, suggesting durable responses with the combination of rituximab and 5F9 – a humanized monoclonal antibody that blocks CD47, an antiphagocytic or “do not eat me” signal overexpressed by most cancers, Ranjana Advani, MD, of Stanford (Calif.) University, and her coauthors wrote.

“The macrophage-mediated activity of 5F9 plus rituximab may serve as an effective new immunotherapy for stimulating the innate immune system,” Dr. Advani and her colleagues reported in the New England Journal of Medicine.

The study included 22 patients, including 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma, who had received a median of four prior therapies. Almost all of the non-Hodgkin lymphomas (21, or 95%) were refractory to rituximab.

All patients received intravenous 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10-30 mg/kg in three dose-escalation cohorts, given until disease progression or lack of clinical benefit. Intravenous rituximab at 375 mg/m² weekly was started on the second week of the first cycle, and then monthly for cycles 2 through 6.

“Substantial antitumor activity” was seen with this chemotherapy-free regimen in a group of heavily pretreated, largely rituximab-refractory patients, Dr. Advani and her coauthors wrote in their report.

The objective response rate was 50%, including a 36% complete response rate in the intent-to-treat analysis. For DLBCL, the rates of objective and complete responses were 40% and 33%, while for follicular lymphoma, they were 71% and 43%.

The median duration of response was not reached in either disease cohort with a median follow-up of 6.2 months for DLBCL and 8.1 months for follicular lymphoma. Of the 11 patients who responded, 10 (91%) were still in response at the time of data cutoff. “Longer follow-up is needed,” the investigators wrote.

Most adverse events were seen within the first few weeks of treatment and mainly included anemia and infusion-related reactions. The anemia was an expected, on-target effect of 5F9 because of selective clearance of older red cells, which was predictable, transient, and mitigated by the maintenance dosing strategy employed in this phase 1b trial.

“As red cells age, they lose CD47 expression and gain expression of prophagocytic signals, leading to homeostatic clearance,” they wrote.

The activity of 5F9 and rituximab is “synergistic” based on the results of previous, preclinical investigations in models of lymphoma, Dr. Advani and her coauthors added.

A phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell non-Hodgkin lymphoma is ongoing, according to their report.

The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.

SOURCE: Advani R et al. N Engl J Med. 2018;379:1711-21.

A macrophage-activating immune checkpoint inhibitor, combined with rituximab therapy, was safe and produced durable complete responses in patients with relapsed or refractory non-Hodgkin lymphoma, according to results of a phase 1b study.

Courtesy Stanford Medicine

Mainly low-grade toxic effects were seen on treatment with Hu5F9-G4 (5F9) and rituximab, which induced responses in more than half of patients, of which more than one-third were complete responses, the study investigators reported.

Most of the responses were ongoing at the time of data cutoff, suggesting durable responses with the combination of rituximab and 5F9 – a humanized monoclonal antibody that blocks CD47, an antiphagocytic or “do not eat me” signal overexpressed by most cancers, Ranjana Advani, MD, of Stanford (Calif.) University, and her coauthors wrote.

“The macrophage-mediated activity of 5F9 plus rituximab may serve as an effective new immunotherapy for stimulating the innate immune system,” Dr. Advani and her colleagues reported in the New England Journal of Medicine.

The study included 22 patients, including 15 with diffuse large B-cell lymphoma (DLBCL) and 7 with follicular lymphoma, who had received a median of four prior therapies. Almost all of the non-Hodgkin lymphomas (21, or 95%) were refractory to rituximab.

All patients received intravenous 5F9 starting with a priming dose of 1 mg/kg followed by weekly maintenance doses of 10-30 mg/kg in three dose-escalation cohorts, given until disease progression or lack of clinical benefit. Intravenous rituximab at 375 mg/m² weekly was started on the second week of the first cycle, and then monthly for cycles 2 through 6.

“Substantial antitumor activity” was seen with this chemotherapy-free regimen in a group of heavily pretreated, largely rituximab-refractory patients, Dr. Advani and her coauthors wrote in their report.

The objective response rate was 50%, including a 36% complete response rate in the intent-to-treat analysis. For DLBCL, the rates of objective and complete responses were 40% and 33%, while for follicular lymphoma, they were 71% and 43%.

The median duration of response was not reached in either disease cohort with a median follow-up of 6.2 months for DLBCL and 8.1 months for follicular lymphoma. Of the 11 patients who responded, 10 (91%) were still in response at the time of data cutoff. “Longer follow-up is needed,” the investigators wrote.

Most adverse events were seen within the first few weeks of treatment and mainly included anemia and infusion-related reactions. The anemia was an expected, on-target effect of 5F9 because of selective clearance of older red cells, which was predictable, transient, and mitigated by the maintenance dosing strategy employed in this phase 1b trial.

“As red cells age, they lose CD47 expression and gain expression of prophagocytic signals, leading to homeostatic clearance,” they wrote.

The activity of 5F9 and rituximab is “synergistic” based on the results of previous, preclinical investigations in models of lymphoma, Dr. Advani and her coauthors added.

A phase 2 trial of 5F9 plus rituximab in relapsed or refractory B-cell non-Hodgkin lymphoma is ongoing, according to their report.

The study was supported by Forty Seven and the Leukemia & Lymphoma Society. Dr. Advani reported disclosures related to Forty Seven, Bristol-Myers Squibb, Pharmacyclics, Seattle Genetics, and Roche/Genentech, among others.

SOURCE: Advani R et al. N Engl J Med. 2018;379:1711-21.

Elderly patients with non-Hodgkin lymphoma (NHL) are more likely to die, but not relapse, within 1 year of allogeneic hematopoietic cell transplantation (alloHCT), compared with younger or middle-age patients, according to investigators.

copyright claudiobaba/iStockPhoto.com

Comorbidities also increased risks of nonrelapse mortality (NRM) at 1 year, but to a lesser extent than that of elderly status, reported lead author Charalampia Kyriakou, MD, PhD, of the department of haematology at University College London Hospital and London North West University Healthcare NHS Trust, and her colleagues.

“Although alloHCT is feasible and effective in very old patients, the increased NRM risk must be taken into account when assessing the indication for alloHCT for NHL in this age group,” the investigators wrote in Biology of Blood and Marrow Transplantation.

This decision is becoming more common, they noted. “With the advent of reduced-intensity conditioning (RIC) strategies and other improvements in transplantation technology, alloHCT is being increasingly considered in elderly patients with [relapsed and refractory] NHL.”

The retrospective study analyzed 3,919 patients with NHL who underwent alloHCT between 2003 and 2013. Patients were sorted into three age groups: young (18-50 years), middle age (51-65 years), or elderly (66-77 years).

Disease types also were reported: 1,461 patients had follicular lymphoma (FL; 37%), 1,192 had diffuse large B cell lymphoma (DLBCL; 30%), 823 had mantle cell lymphoma (MCL; 21%), and 443 had peripheral T cell lymphoma (PTCL; 11%).

At the time of alloHCT, about 85% of patients were chemosensitive, with the remainder being chemorefractory. The age groups had similar patient characteristics, with exceptions noted for unrelated donors, MCL, and RIC, which became increasingly overrepresented with age.

The results showed that NRM at 1 year was 13% for young patients, 20% for middle-age patients, and 33% for elderly patients (P less than .001). Overall survival at 3 years followed an inverse trend, decreasing with age from 60% in young patients to 54% in middle-age patients, before dropping more dramatically to 38% in the elderly (P less than .001).

In contrast to these significant associations between age and survival, relapse risk at 3 years remained relatively consistent, with young patients at 30%, middle-age patients at 31%, and elderly patients at 28% (P = .355).

The investigators noted that the risk of NRM increased most dramatically between middle age and old age, with less significant differences between the middle-age and young groups. They suggested that “age per se should have a limited impact on the indication for alloHCT for NHL in patients up to age 65 years.”

The increased risk with elderly status could not be fully explained by comorbidities, although these were more common in elderly patients. After analyzing information from a subset of patients, the investigators concluded that “the presence of comorbidities is a significant risk factor for NRM and survival, but this does not fully explain the outcome disadvantages in our [elderly] group.” Therefore, age remains an independent risk factor.

“The information provided in this cohort of patients with NHL, the largest reported to date, is useful and relevant, especially in the era of evolving therapies,” the investigators wrote. They added that the information is “even more relevant now with the availability of treatment with ... chimeric antigen receptor (CAR) T cells ... after relapse post-alloHCT.”

The investigators reported having no financial disclosures.

SOURCE: Kyriakou C et al. Biol Blood Marrow Transplant. 2018 Sep 13. doi: 10.1016/j.bbmt.2018.08.025.

Elderly patients with non-Hodgkin lymphoma (NHL) are more likely to die, but not relapse, within 1 year of allogeneic hematopoietic cell transplantation (alloHCT), compared with younger or middle-age patients, according to investigators.

copyright claudiobaba/iStockPhoto.com

Comorbidities also increased risks of nonrelapse mortality (NRM) at 1 year, but to a lesser extent than that of elderly status, reported lead author Charalampia Kyriakou, MD, PhD, of the department of haematology at University College London Hospital and London North West University Healthcare NHS Trust, and her colleagues.

“Although alloHCT is feasible and effective in very old patients, the increased NRM risk must be taken into account when assessing the indication for alloHCT for NHL in this age group,” the investigators wrote in Biology of Blood and Marrow Transplantation.

This decision is becoming more common, they noted. “With the advent of reduced-intensity conditioning (RIC) strategies and other improvements in transplantation technology, alloHCT is being increasingly considered in elderly patients with [relapsed and refractory] NHL.”

The retrospective study analyzed 3,919 patients with NHL who underwent alloHCT between 2003 and 2013. Patients were sorted into three age groups: young (18-50 years), middle age (51-65 years), or elderly (66-77 years).

Disease types also were reported: 1,461 patients had follicular lymphoma (FL; 37%), 1,192 had diffuse large B cell lymphoma (DLBCL; 30%), 823 had mantle cell lymphoma (MCL; 21%), and 443 had peripheral T cell lymphoma (PTCL; 11%).

At the time of alloHCT, about 85% of patients were chemosensitive, with the remainder being chemorefractory. The age groups had similar patient characteristics, with exceptions noted for unrelated donors, MCL, and RIC, which became increasingly overrepresented with age.

The results showed that NRM at 1 year was 13% for young patients, 20% for middle-age patients, and 33% for elderly patients (P less than .001). Overall survival at 3 years followed an inverse trend, decreasing with age from 60% in young patients to 54% in middle-age patients, before dropping more dramatically to 38% in the elderly (P less than .001).

In contrast to these significant associations between age and survival, relapse risk at 3 years remained relatively consistent, with young patients at 30%, middle-age patients at 31%, and elderly patients at 28% (P = .355).

The investigators noted that the risk of NRM increased most dramatically between middle age and old age, with less significant differences between the middle-age and young groups. They suggested that “age per se should have a limited impact on the indication for alloHCT for NHL in patients up to age 65 years.”

The increased risk with elderly status could not be fully explained by comorbidities, although these were more common in elderly patients. After analyzing information from a subset of patients, the investigators concluded that “the presence of comorbidities is a significant risk factor for NRM and survival, but this does not fully explain the outcome disadvantages in our [elderly] group.” Therefore, age remains an independent risk factor.

“The information provided in this cohort of patients with NHL, the largest reported to date, is useful and relevant, especially in the era of evolving therapies,” the investigators wrote. They added that the information is “even more relevant now with the availability of treatment with ... chimeric antigen receptor (CAR) T cells ... after relapse post-alloHCT.”

The investigators reported having no financial disclosures.

SOURCE: Kyriakou C et al. Biol Blood Marrow Transplant. 2018 Sep 13. doi: 10.1016/j.bbmt.2018.08.025.

Elderly patients with non-Hodgkin lymphoma (NHL) are more likely to die, but not relapse, within 1 year of allogeneic hematopoietic cell transplantation (alloHCT), compared with younger or middle-age patients, according to investigators.

copyright claudiobaba/iStockPhoto.com

Comorbidities also increased risks of nonrelapse mortality (NRM) at 1 year, but to a lesser extent than that of elderly status, reported lead author Charalampia Kyriakou, MD, PhD, of the department of haematology at University College London Hospital and London North West University Healthcare NHS Trust, and her colleagues.

“Although alloHCT is feasible and effective in very old patients, the increased NRM risk must be taken into account when assessing the indication for alloHCT for NHL in this age group,” the investigators wrote in Biology of Blood and Marrow Transplantation.

This decision is becoming more common, they noted. “With the advent of reduced-intensity conditioning (RIC) strategies and other improvements in transplantation technology, alloHCT is being increasingly considered in elderly patients with [relapsed and refractory] NHL.”

The retrospective study analyzed 3,919 patients with NHL who underwent alloHCT between 2003 and 2013. Patients were sorted into three age groups: young (18-50 years), middle age (51-65 years), or elderly (66-77 years).

Disease types also were reported: 1,461 patients had follicular lymphoma (FL; 37%), 1,192 had diffuse large B cell lymphoma (DLBCL; 30%), 823 had mantle cell lymphoma (MCL; 21%), and 443 had peripheral T cell lymphoma (PTCL; 11%).

At the time of alloHCT, about 85% of patients were chemosensitive, with the remainder being chemorefractory. The age groups had similar patient characteristics, with exceptions noted for unrelated donors, MCL, and RIC, which became increasingly overrepresented with age.

The results showed that NRM at 1 year was 13% for young patients, 20% for middle-age patients, and 33% for elderly patients (P less than .001). Overall survival at 3 years followed an inverse trend, decreasing with age from 60% in young patients to 54% in middle-age patients, before dropping more dramatically to 38% in the elderly (P less than .001).

In contrast to these significant associations between age and survival, relapse risk at 3 years remained relatively consistent, with young patients at 30%, middle-age patients at 31%, and elderly patients at 28% (P = .355).

The investigators noted that the risk of NRM increased most dramatically between middle age and old age, with less significant differences between the middle-age and young groups. They suggested that “age per se should have a limited impact on the indication for alloHCT for NHL in patients up to age 65 years.”

The increased risk with elderly status could not be fully explained by comorbidities, although these were more common in elderly patients. After analyzing information from a subset of patients, the investigators concluded that “the presence of comorbidities is a significant risk factor for NRM and survival, but this does not fully explain the outcome disadvantages in our [elderly] group.” Therefore, age remains an independent risk factor.

“The information provided in this cohort of patients with NHL, the largest reported to date, is useful and relevant, especially in the era of evolving therapies,” the investigators wrote. They added that the information is “even more relevant now with the availability of treatment with ... chimeric antigen receptor (CAR) T cells ... after relapse post-alloHCT.”

The investigators reported having no financial disclosures.

SOURCE: Kyriakou C et al. Biol Blood Marrow Transplant. 2018 Sep 13. doi: 10.1016/j.bbmt.2018.08.025.

Entospletinib, a selective inhibitor of spleen tyrosine kinase (Syk), showed a dismal rate of progression-free survival and a high rate of adverse events in a cohort of previously treated patients with diffuse large B-cell lymphoma (DLBCL).

Nephron/Wikimedia Commons/CC BY-SA 3.0

Entospletinib was evaluated in an open-label, single-agent, phase 2 trial (NCT01799889) with five relapsed/refractory patient cohorts: chronic lymphocytic leukemia (CLL), follicular lymphoma, other indolent non-Hodgkin lymphomas, mantle cell lymphoma, and DLBCL.

John M. Burke, MD, of Rocky Mountain Cancer Centers in Aurora, Colo., and his colleagues reported on the current analysis, which looked specifically at the 43 patients in the trial with previously treated DLBCL. Patients received at least one starting dose of 800 mg of entospletinib orally twice daily. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.

In a previous report on the relapsed/refractory CLL cohort, the investigational agent demonstrated clinical activity with acceptable toxicity (Blood. 2015 Apr 9;125[15]:2336-43).

In the current report, the rate of progression-free survival (PFS) at 16 weeks was 3.6% and the median PFS was 1.5 months. None of the patients in the study achieved a complete or partial response to treatment, and just five patients had stable disease.

All patients in the study eventually discontinued treatment and the median treatment duration was 1 month.

“The lack of activity of Syk inhibition in patients with relapsed DLBCL is in contrast to what would have been expected from preclinical data,” the investigators wrote. “Although it is unclear why entospletinib monotherapy lacked activity in the present study, it is possible that resistance to Syk inhibition played a role. Potential mechanisms of resistance of DLBCL to Syk inhibition include transcriptional upregulation of Syk mediated by FOXO1 and PTEN depletion.”

The investigators said that Syk inhibition in combination with BCL2 inhibitors could potentially overcome this resistance. Another approach, they suggested, would be to offer entospletinib in combination with Janus kinase (JAK) 1/3 inhibition.

“Based on results of the preclinical data, the efficacy of entospletinib in combination will be evaluated in future clinical trials,” the investigators wrote.

The rate of adverse events was high in the DLBCL cohort. Forty-two patients (98%) experienced an adverse event and nearly three-quarters experienced a grade 3 event. Overall, 30% of the grade 3 adverse events were related to treatment. More than 40% of patients interrupted treatment because of adverse events, and 19% discontinued. Four patients experienced an adverse event that led to death.

While the lack of clinical activity may have surprised investigators, the safety profile was in line with other patient cohorts in the phase 2 study. In the CLL and indolent non-Hodgkin lymphoma cohorts, the rates of treatment interruption were 45% and 54%, respectively.

The study was supported by Gilead Sciences. Dr. Burke reported relationships with Gilead and other companies.

mschneider@mdedge.com

SOURCE: Burke JM et al. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):e327-e331.

Entospletinib, a selective inhibitor of spleen tyrosine kinase (Syk), showed a dismal rate of progression-free survival and a high rate of adverse events in a cohort of previously treated patients with diffuse large B-cell lymphoma (DLBCL).

Nephron/Wikimedia Commons/CC BY-SA 3.0

Entospletinib was evaluated in an open-label, single-agent, phase 2 trial (NCT01799889) with five relapsed/refractory patient cohorts: chronic lymphocytic leukemia (CLL), follicular lymphoma, other indolent non-Hodgkin lymphomas, mantle cell lymphoma, and DLBCL.

John M. Burke, MD, of Rocky Mountain Cancer Centers in Aurora, Colo., and his colleagues reported on the current analysis, which looked specifically at the 43 patients in the trial with previously treated DLBCL. Patients received at least one starting dose of 800 mg of entospletinib orally twice daily. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.

In a previous report on the relapsed/refractory CLL cohort, the investigational agent demonstrated clinical activity with acceptable toxicity (Blood. 2015 Apr 9;125[15]:2336-43).

In the current report, the rate of progression-free survival (PFS) at 16 weeks was 3.6% and the median PFS was 1.5 months. None of the patients in the study achieved a complete or partial response to treatment, and just five patients had stable disease.

All patients in the study eventually discontinued treatment and the median treatment duration was 1 month.

“The lack of activity of Syk inhibition in patients with relapsed DLBCL is in contrast to what would have been expected from preclinical data,” the investigators wrote. “Although it is unclear why entospletinib monotherapy lacked activity in the present study, it is possible that resistance to Syk inhibition played a role. Potential mechanisms of resistance of DLBCL to Syk inhibition include transcriptional upregulation of Syk mediated by FOXO1 and PTEN depletion.”

The investigators said that Syk inhibition in combination with BCL2 inhibitors could potentially overcome this resistance. Another approach, they suggested, would be to offer entospletinib in combination with Janus kinase (JAK) 1/3 inhibition.

“Based on results of the preclinical data, the efficacy of entospletinib in combination will be evaluated in future clinical trials,” the investigators wrote.

The rate of adverse events was high in the DLBCL cohort. Forty-two patients (98%) experienced an adverse event and nearly three-quarters experienced a grade 3 event. Overall, 30% of the grade 3 adverse events were related to treatment. More than 40% of patients interrupted treatment because of adverse events, and 19% discontinued. Four patients experienced an adverse event that led to death.

While the lack of clinical activity may have surprised investigators, the safety profile was in line with other patient cohorts in the phase 2 study. In the CLL and indolent non-Hodgkin lymphoma cohorts, the rates of treatment interruption were 45% and 54%, respectively.

The study was supported by Gilead Sciences. Dr. Burke reported relationships with Gilead and other companies.

mschneider@mdedge.com

SOURCE: Burke JM et al. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):e327-e331.

Entospletinib, a selective inhibitor of spleen tyrosine kinase (Syk), showed a dismal rate of progression-free survival and a high rate of adverse events in a cohort of previously treated patients with diffuse large B-cell lymphoma (DLBCL).

Nephron/Wikimedia Commons/CC BY-SA 3.0

Entospletinib was evaluated in an open-label, single-agent, phase 2 trial (NCT01799889) with five relapsed/refractory patient cohorts: chronic lymphocytic leukemia (CLL), follicular lymphoma, other indolent non-Hodgkin lymphomas, mantle cell lymphoma, and DLBCL.

John M. Burke, MD, of Rocky Mountain Cancer Centers in Aurora, Colo., and his colleagues reported on the current analysis, which looked specifically at the 43 patients in the trial with previously treated DLBCL. Patients received at least one starting dose of 800 mg of entospletinib orally twice daily. The findings were published in Clinical Lymphoma, Myeloma & Leukemia.

In a previous report on the relapsed/refractory CLL cohort, the investigational agent demonstrated clinical activity with acceptable toxicity (Blood. 2015 Apr 9;125[15]:2336-43).

In the current report, the rate of progression-free survival (PFS) at 16 weeks was 3.6% and the median PFS was 1.5 months. None of the patients in the study achieved a complete or partial response to treatment, and just five patients had stable disease.

All patients in the study eventually discontinued treatment and the median treatment duration was 1 month.

“The lack of activity of Syk inhibition in patients with relapsed DLBCL is in contrast to what would have been expected from preclinical data,” the investigators wrote. “Although it is unclear why entospletinib monotherapy lacked activity in the present study, it is possible that resistance to Syk inhibition played a role. Potential mechanisms of resistance of DLBCL to Syk inhibition include transcriptional upregulation of Syk mediated by FOXO1 and PTEN depletion.”

The investigators said that Syk inhibition in combination with BCL2 inhibitors could potentially overcome this resistance. Another approach, they suggested, would be to offer entospletinib in combination with Janus kinase (JAK) 1/3 inhibition.

“Based on results of the preclinical data, the efficacy of entospletinib in combination will be evaluated in future clinical trials,” the investigators wrote.

The rate of adverse events was high in the DLBCL cohort. Forty-two patients (98%) experienced an adverse event and nearly three-quarters experienced a grade 3 event. Overall, 30% of the grade 3 adverse events were related to treatment. More than 40% of patients interrupted treatment because of adverse events, and 19% discontinued. Four patients experienced an adverse event that led to death.

While the lack of clinical activity may have surprised investigators, the safety profile was in line with other patient cohorts in the phase 2 study. In the CLL and indolent non-Hodgkin lymphoma cohorts, the rates of treatment interruption were 45% and 54%, respectively.

The study was supported by Gilead Sciences. Dr. Burke reported relationships with Gilead and other companies.

mschneider@mdedge.com

SOURCE: Burke JM et al. Clin Lymphoma Myeloma Leuk. 2018 Aug;18(8):e327-e331.

Image by Michael Bonert

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to cerdulatinib for the treatment of peripheral T-cell lymphoma (PTCL).

Cerdulatinib is an oral Syk/JAK inhibitor being developed by Portola Pharmaceuticals, Inc.

Preclinical data have suggested an important role for Syk and JAK in PTCL tumor survival, and cerdulatinib is currently under evaluation in a phase 2a study of patients with PTCL and other non-Hodgkin lymphomas.

Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) earlier this year.

At that time, the trial had enrolled 114 patients, 25 of them with PTCL. The patients received cerdulatinib at 25, 30, or 35 mg twice daily.

The objective response rate was 35% among the PTCL patients. All seven responders had a complete response, and 11 PTCL patients were still on cerdulatinib at the time of the presentation.

Grade 3 or higher adverse events observed in all evaluable patients included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).

There were five deaths due to sepsis or septic shock (three of which were concomitant with pneumonia) that were considered related to cerdulatinib.

Three of the deaths occurred in patients with chronic lymphocytic leukemia, one in a patient with diffuse large B-cell lymphoma, and one in a patient with follicular lymphoma.

The deaths occurred early on in the trial, and researchers have since taken steps—dose reductions, monitoring, and antibiotic prophylaxis—to prevent additional deaths.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Michael Bonert

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to cerdulatinib for the treatment of peripheral T-cell lymphoma (PTCL).

Cerdulatinib is an oral Syk/JAK inhibitor being developed by Portola Pharmaceuticals, Inc.

Preclinical data have suggested an important role for Syk and JAK in PTCL tumor survival, and cerdulatinib is currently under evaluation in a phase 2a study of patients with PTCL and other non-Hodgkin lymphomas.

Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) earlier this year.

At that time, the trial had enrolled 114 patients, 25 of them with PTCL. The patients received cerdulatinib at 25, 30, or 35 mg twice daily.

The objective response rate was 35% among the PTCL patients. All seven responders had a complete response, and 11 PTCL patients were still on cerdulatinib at the time of the presentation.

Grade 3 or higher adverse events observed in all evaluable patients included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).

There were five deaths due to sepsis or septic shock (three of which were concomitant with pneumonia) that were considered related to cerdulatinib.

Three of the deaths occurred in patients with chronic lymphocytic leukemia, one in a patient with diffuse large B-cell lymphoma, and one in a patient with follicular lymphoma.

The deaths occurred early on in the trial, and researchers have since taken steps—dose reductions, monitoring, and antibiotic prophylaxis—to prevent additional deaths.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Michael Bonert

The U.S. Food and Drug Administration (FDA) has granted orphan drug designation to cerdulatinib for the treatment of peripheral T-cell lymphoma (PTCL).

Cerdulatinib is an oral Syk/JAK inhibitor being developed by Portola Pharmaceuticals, Inc.

Preclinical data have suggested an important role for Syk and JAK in PTCL tumor survival, and cerdulatinib is currently under evaluation in a phase 2a study of patients with PTCL and other non-Hodgkin lymphomas.

Results from this trial were presented at the 23rd Congress of the European Hematology Association (EHA) earlier this year.

At that time, the trial had enrolled 114 patients, 25 of them with PTCL. The patients received cerdulatinib at 25, 30, or 35 mg twice daily.

The objective response rate was 35% among the PTCL patients. All seven responders had a complete response, and 11 PTCL patients were still on cerdulatinib at the time of the presentation.

Grade 3 or higher adverse events observed in all evaluable patients included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).

There were five deaths due to sepsis or septic shock (three of which were concomitant with pneumonia) that were considered related to cerdulatinib.

Three of the deaths occurred in patients with chronic lymphocytic leukemia, one in a patient with diffuse large B-cell lymphoma, and one in a patient with follicular lymphoma.

The deaths occurred early on in the trial, and researchers have since taken steps—dose reductions, monitoring, and antibiotic prophylaxis—to prevent additional deaths.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the United States.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Advanced indolent lymphoma patients can be treated with a rituximab-containing regimen as first-line therapy and, in some cases, skip chemotherapy altogether, a study with 10 years of follow-up data suggests.

Patho/Wikimedia Commons/CC BY-SA 3.0

After a median of 10.6 years’ follow-up, almost three-quarters of patients (73%) in the study were alive, and 36% never required chemotherapy.

“This [overall survival] is at least as good as that observed in modern immunochemotherapy trials,” Sandra Lockmer, MD, of Karolinska University Hospital in Stockholm and her colleagues reported in the Journal of Clinical Oncology.

The study included 321 patients who were previously untreated and had been enrolled in two randomized clinical trials performed by the Nordic Lymphoma Group. The trials randomized patients to receive either rituximab monotherapy or rituximab combined with interferon alfa-2a. Neither trial used up-front chemotherapy.

Patients included in the follow-up analysis had follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, or indolent lymphoma not otherwise specified.

The overall survival rate at 10 years after trial assignment was 75% and 66% after 15 years. Similarly, the lymphoma-specific survival rate was 81% at 10 years after trial assignment and 77% at 15 years, the researchers reported.

Overall, 117 patients did not require treatment with chemotherapy, but 24 patients were further treated with antibodies and/or radiation. Of the 93 patients who received no additional therapies after frontline treatment, 9 patients died from causes unrelated to their lymphoma.

Among the 237 patients who failed initial treatment, the median time to treatment failure was 1.5 years.

In terms of transformation to aggressive lymphoma, the rate was 2.4%/person-year overall. The cumulative risk of transformation was 20% at 10 years after trial assignment and 24% at 15 years.

The study was funded in part by the Stockholm County Council and by the Nordic Lymphoma Group. The trials analyzed in the study were supported by Roche. Dr. Lockmer reported having no financial disclosures. Her coauthors reported relationships with Novartis, Gilead, Roche, and Takeda, among others.

mschneider@mdedge.com

SOURCE: Lockmer S et al. J Clin Oncol. 2018 Oct 4:JCO1800262. doi: 10.1200/JCO.18.00262.

Advanced indolent lymphoma patients can be treated with a rituximab-containing regimen as first-line therapy and, in some cases, skip chemotherapy altogether, a study with 10 years of follow-up data suggests.

Patho/Wikimedia Commons/CC BY-SA 3.0

After a median of 10.6 years’ follow-up, almost three-quarters of patients (73%) in the study were alive, and 36% never required chemotherapy.

“This [overall survival] is at least as good as that observed in modern immunochemotherapy trials,” Sandra Lockmer, MD, of Karolinska University Hospital in Stockholm and her colleagues reported in the Journal of Clinical Oncology.

The study included 321 patients who were previously untreated and had been enrolled in two randomized clinical trials performed by the Nordic Lymphoma Group. The trials randomized patients to receive either rituximab monotherapy or rituximab combined with interferon alfa-2a. Neither trial used up-front chemotherapy.

Patients included in the follow-up analysis had follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, or indolent lymphoma not otherwise specified.

The overall survival rate at 10 years after trial assignment was 75% and 66% after 15 years. Similarly, the lymphoma-specific survival rate was 81% at 10 years after trial assignment and 77% at 15 years, the researchers reported.

Overall, 117 patients did not require treatment with chemotherapy, but 24 patients were further treated with antibodies and/or radiation. Of the 93 patients who received no additional therapies after frontline treatment, 9 patients died from causes unrelated to their lymphoma.

Among the 237 patients who failed initial treatment, the median time to treatment failure was 1.5 years.

In terms of transformation to aggressive lymphoma, the rate was 2.4%/person-year overall. The cumulative risk of transformation was 20% at 10 years after trial assignment and 24% at 15 years.

The study was funded in part by the Stockholm County Council and by the Nordic Lymphoma Group. The trials analyzed in the study were supported by Roche. Dr. Lockmer reported having no financial disclosures. Her coauthors reported relationships with Novartis, Gilead, Roche, and Takeda, among others.

mschneider@mdedge.com

SOURCE: Lockmer S et al. J Clin Oncol. 2018 Oct 4:JCO1800262. doi: 10.1200/JCO.18.00262.

Advanced indolent lymphoma patients can be treated with a rituximab-containing regimen as first-line therapy and, in some cases, skip chemotherapy altogether, a study with 10 years of follow-up data suggests.

Patho/Wikimedia Commons/CC BY-SA 3.0

After a median of 10.6 years’ follow-up, almost three-quarters of patients (73%) in the study were alive, and 36% never required chemotherapy.

“This [overall survival] is at least as good as that observed in modern immunochemotherapy trials,” Sandra Lockmer, MD, of Karolinska University Hospital in Stockholm and her colleagues reported in the Journal of Clinical Oncology.

The study included 321 patients who were previously untreated and had been enrolled in two randomized clinical trials performed by the Nordic Lymphoma Group. The trials randomized patients to receive either rituximab monotherapy or rituximab combined with interferon alfa-2a. Neither trial used up-front chemotherapy.

Patients included in the follow-up analysis had follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, or indolent lymphoma not otherwise specified.

The overall survival rate at 10 years after trial assignment was 75% and 66% after 15 years. Similarly, the lymphoma-specific survival rate was 81% at 10 years after trial assignment and 77% at 15 years, the researchers reported.

Overall, 117 patients did not require treatment with chemotherapy, but 24 patients were further treated with antibodies and/or radiation. Of the 93 patients who received no additional therapies after frontline treatment, 9 patients died from causes unrelated to their lymphoma.

Among the 237 patients who failed initial treatment, the median time to treatment failure was 1.5 years.

In terms of transformation to aggressive lymphoma, the rate was 2.4%/person-year overall. The cumulative risk of transformation was 20% at 10 years after trial assignment and 24% at 15 years.

The study was funded in part by the Stockholm County Council and by the Nordic Lymphoma Group. The trials analyzed in the study were supported by Roche. Dr. Lockmer reported having no financial disclosures. Her coauthors reported relationships with Novartis, Gilead, Roche, and Takeda, among others.

mschneider@mdedge.com

SOURCE: Lockmer S et al. J Clin Oncol. 2018 Oct 4:JCO1800262. doi: 10.1200/JCO.18.00262.

The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.

jensmith@mdedge.com

The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.

jensmith@mdedge.com

The U.S. Food and Drug Administration has lifted the partial clinical hold on trials of tazemetostat, an EZH2 inhibitor being developed to treat solid tumors and lymphomas, according to a press release from the drug’s developer Epizyme.

jensmith@mdedge.com

The Food and Drug Administration has approved duvelisib (Copiktra), a dual PI3K delta/gamma inhibitor, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma.

Duvelisib has full FDA approval to treat adults with relapsed or refractory CLL/SLL who have received at least two prior therapies. Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.

Accelerated approval is based on a surrogate or intermediate endpoint – in this case, overall response rate – that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.

Duvelisib will be available in the U.S. immediately, according to Verastem, the company marketing the drug. The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug – infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.

The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.

The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. The DUO trial included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2,000 mg).

Efficacy results are based on patients who had received at least two prior therapies, including 95 patients in the duvelisib arm and 101 in the ofatumumab arm. The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.

The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab.

The safety results include all patients treated with duvelisib or ofatumumab in this trial. In the duvelisib arm, 12% of patients had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab. Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection and diarrhea/colitis. The DYNAMO trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy. There were 83 patients with FL.

Patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.

The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.

Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.

Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.

jensmith@mdedge.com

The Food and Drug Administration has approved duvelisib (Copiktra), a dual PI3K delta/gamma inhibitor, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma.

Duvelisib has full FDA approval to treat adults with relapsed or refractory CLL/SLL who have received at least two prior therapies. Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.

Accelerated approval is based on a surrogate or intermediate endpoint – in this case, overall response rate – that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.

Duvelisib will be available in the U.S. immediately, according to Verastem, the company marketing the drug. The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug – infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.

The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.

The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. The DUO trial included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2,000 mg).

Efficacy results are based on patients who had received at least two prior therapies, including 95 patients in the duvelisib arm and 101 in the ofatumumab arm. The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.

The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab.

The safety results include all patients treated with duvelisib or ofatumumab in this trial. In the duvelisib arm, 12% of patients had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab. Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection and diarrhea/colitis. The DYNAMO trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy. There were 83 patients with FL.

Patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.

The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.

Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.

Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.

jensmith@mdedge.com

The Food and Drug Administration has approved duvelisib (Copiktra), a dual PI3K delta/gamma inhibitor, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and follicular lymphoma.

Duvelisib has full FDA approval to treat adults with relapsed or refractory CLL/SLL who have received at least two prior therapies. Duvelisib also has accelerated approval to treat adults with relapsed or refractory follicular lymphoma (FL) who have received at least two prior systemic therapies.

Accelerated approval is based on a surrogate or intermediate endpoint – in this case, overall response rate – that is reasonably likely to predict clinical benefit. Continued approval of duvelisib in FL may be contingent upon results of confirmatory trials verifying that the drug provides a clinical benefit.

Duvelisib will be available in the U.S. immediately, according to Verastem, the company marketing the drug. The prescribing information for duvelisib includes a boxed warning detailing four fatal and/or serious toxicities associated with the drug – infections, diarrhea or colitis, cutaneous reactions, and pneumonitis. Verastem said it is implementing an informational risk evaluation and mitigation strategy to provide appropriate dosing and safety information for duvelisib.

The recommended dose of duvelisib is 25 mg orally twice daily, taken continuously in 28-day treatment cycles.

The FDA’s approval of duvelisib is supported by data from the phase 3 DUO trial and the phase 2 DYNAMO trial. The DUO trial included 319 patients with CLL (n=312) or SLL (n=7) who had received at least one prior therapy. They were randomized to receive either duvelisib (25 mg orally twice daily) or ofatumumab (initial infusion of 300 mg followed by 7 weekly infusions and 4 monthly infusions of 2,000 mg).

Efficacy results are based on patients who had received at least two prior therapies, including 95 patients in the duvelisib arm and 101 in the ofatumumab arm. The overall response rate was 78% in the duvelisib arm and 39% in the ofatumumab arm. All responses in both arms were partial responses.

The median progression-free survival was 16.4 months with duvelisib and 9.1 months with ofatumumab.

The safety results include all patients treated with duvelisib or ofatumumab in this trial. In the duvelisib arm, 12% of patients had fatal adverse events (AEs) within 30 days of the last dose. The same was true of 4% of patients treated with ofatumumab. Serious AEs occurred in 73% of patients treated with duvelisib. The most common were infection and diarrhea/colitis. The DYNAMO trial enrolled patients with indolent non-Hodgkin lymphoma whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy. There were 83 patients with FL.

Patients received duvelisib at 25 mg orally twice daily until disease progression or unacceptable toxicity.

The overall response rate was 42%. One patient achieved a complete response, and 34 had a partial response.

Forty-three percent of responders maintained their response at 6 months, and 17% maintained their response at 12 months.

Serious AEs occurred in 58% of FL patients. The most common were diarrhea/colitis, pneumonia, renal insufficiency, rash, and sepsis.

jensmith@mdedge.com

follicular lymphoma

A subset of follicular lymphoma (FL) patients managed with watchful waiting are vulnerable to organ dysfunction and transformation, according to research published in Clinical Lymphoma, Myeloma & Leukemia.

In a retrospective study, about 24% of FL patients managed with watchful waiting developed significant organ dysfunction or transformation at first progression over 8.2 years of follow-up.

Organ dysfunction and transformation were associated with significantly worse overall survival (OS) that could not be predicted based on baseline characteristics.

Gwynivere A. Davies, MD, of the University of Calgary in Alberta, Canada, and her colleagues conducted this study using  data from the Alberta Lymphoma Database. The team gathered data on patients with grade 1-3a FL who were diagnosed between 1994 and 2011.

The investigators identified 238 patients who were initially managed with watchful waiting. The patients had a median age of 54.1 years (range, 24.7-69.9) at diagnosis, and 83.2% were advanced stage.

The 10-year OS rate for these patients was 81.2%. At a median follow-up of 98.5 months, 71% (n=169) of patients had progressed and required therapy.

At the time of progression, 24.4% of patients (n=58) had organ dysfunction and/or transformation. The median time to organ dysfunction/transformation was 29.9 months.

These adverse outcomes were significantly associated with inferior OS. The 10-year OS rate was 65.4% for patients with transformation at progression and 83.2% for those without transformation (P=0.0017).

The 10-year OS rate was 71.5% for those with organ dysfunction at progression and 82.7% for those without organ dysfunction (P=0.028).

Comparison to treated patients

The investigators also looked at a comparison group of 236 FL patients managed with immediate rituximab-based chemotherapy (R-chemo), most of whom were scheduled to receive (72.9%) rituximab maintenance. Their median age was 52.1 (range, 27.3-65.4), and most (82.6%) had advanced stage disease.

At a median follow-up of 100.2 months, the median progression-free survival (PFS) was not reached. The 10-year OS rate was 84%.

The 10-year PFS rate after first R-chemo was 57.1% for patients who received immediate R-chemo (n=236) and 50.5% for patients who were initially managed with watchful waiting and proceeded to R-chemo (n=133; P=0.506). This was not affected by rituximab maintenance.

The investigators noted that OS measured from diagnosis was not affected by initial watchful waiting.

However, in a landmark analysis, OS was inferior when measured from R-chemo at first progression for watchful waiting recipients compared to patients who received immediate R-chemo. The 10-year OS rates were 74.4% and 84.0%, respectively (P=0.02).

The risk of transformation at first progression was significantly different between the groups. At 10 years, the rate of transformation was 25.5% in the watchful waiting group and 6.3% in the immediate R-chemo group (P<0.0001).

The investigators said these findings, taken together, suggest changes may be warranted for FL patients managed with watchful waiting.

“Consideration should be given to implementing standardized follow-up imaging, with early initiation of rituximab-based therapy if there is evidence of progression in an attempt to prevent these potentially clinically impactful events [i.e., organ dysfunction and transformation],” Dr. Davies and her coauthors wrote.

Dr. Davies reported no financial disclosures. Her coauthors reported disclosures related to Janssen, Gilead Sciences, Lundbeck, Roche, AbbVie, Amgen, Seattle Genetics, Bristol-Myers Squibb, Servier Laboratories, and Merck.

follicular lymphoma

A subset of follicular lymphoma (FL) patients managed with watchful waiting are vulnerable to organ dysfunction and transformation, according to research published in Clinical Lymphoma, Myeloma & Leukemia.

In a retrospective study, about 24% of FL patients managed with watchful waiting developed significant organ dysfunction or transformation at first progression over 8.2 years of follow-up.

Organ dysfunction and transformation were associated with significantly worse overall survival (OS) that could not be predicted based on baseline characteristics.

Gwynivere A. Davies, MD, of the University of Calgary in Alberta, Canada, and her colleagues conducted this study using  data from the Alberta Lymphoma Database. The team gathered data on patients with grade 1-3a FL who were diagnosed between 1994 and 2011.

The investigators identified 238 patients who were initially managed with watchful waiting. The patients had a median age of 54.1 years (range, 24.7-69.9) at diagnosis, and 83.2% were advanced stage.

The 10-year OS rate for these patients was 81.2%. At a median follow-up of 98.5 months, 71% (n=169) of patients had progressed and required therapy.

At the time of progression, 24.4% of patients (n=58) had organ dysfunction and/or transformation. The median time to organ dysfunction/transformation was 29.9 months.

These adverse outcomes were significantly associated with inferior OS. The 10-year OS rate was 65.4% for patients with transformation at progression and 83.2% for those without transformation (P=0.0017).

The 10-year OS rate was 71.5% for those with organ dysfunction at progression and 82.7% for those without organ dysfunction (P=0.028).

Comparison to treated patients

The investigators also looked at a comparison group of 236 FL patients managed with immediate rituximab-based chemotherapy (R-chemo), most of whom were scheduled to receive (72.9%) rituximab maintenance. Their median age was 52.1 (range, 27.3-65.4), and most (82.6%) had advanced stage disease.

At a median follow-up of 100.2 months, the median progression-free survival (PFS) was not reached. The 10-year OS rate was 84%.

The 10-year PFS rate after first R-chemo was 57.1% for patients who received immediate R-chemo (n=236) and 50.5% for patients who were initially managed with watchful waiting and proceeded to R-chemo (n=133; P=0.506). This was not affected by rituximab maintenance.

The investigators noted that OS measured from diagnosis was not affected by initial watchful waiting.

However, in a landmark analysis, OS was inferior when measured from R-chemo at first progression for watchful waiting recipients compared to patients who received immediate R-chemo. The 10-year OS rates were 74.4% and 84.0%, respectively (P=0.02).

The risk of transformation at first progression was significantly different between the groups. At 10 years, the rate of transformation was 25.5% in the watchful waiting group and 6.3% in the immediate R-chemo group (P<0.0001).

The investigators said these findings, taken together, suggest changes may be warranted for FL patients managed with watchful waiting.

“Consideration should be given to implementing standardized follow-up imaging, with early initiation of rituximab-based therapy if there is evidence of progression in an attempt to prevent these potentially clinically impactful events [i.e., organ dysfunction and transformation],” Dr. Davies and her coauthors wrote.

Dr. Davies reported no financial disclosures. Her coauthors reported disclosures related to Janssen, Gilead Sciences, Lundbeck, Roche, AbbVie, Amgen, Seattle Genetics, Bristol-Myers Squibb, Servier Laboratories, and Merck.

follicular lymphoma

A subset of follicular lymphoma (FL) patients managed with watchful waiting are vulnerable to organ dysfunction and transformation, according to research published in Clinical Lymphoma, Myeloma & Leukemia.

In a retrospective study, about 24% of FL patients managed with watchful waiting developed significant organ dysfunction or transformation at first progression over 8.2 years of follow-up.

Organ dysfunction and transformation were associated with significantly worse overall survival (OS) that could not be predicted based on baseline characteristics.

Gwynivere A. Davies, MD, of the University of Calgary in Alberta, Canada, and her colleagues conducted this study using  data from the Alberta Lymphoma Database. The team gathered data on patients with grade 1-3a FL who were diagnosed between 1994 and 2011.

The investigators identified 238 patients who were initially managed with watchful waiting. The patients had a median age of 54.1 years (range, 24.7-69.9) at diagnosis, and 83.2% were advanced stage.

The 10-year OS rate for these patients was 81.2%. At a median follow-up of 98.5 months, 71% (n=169) of patients had progressed and required therapy.

At the time of progression, 24.4% of patients (n=58) had organ dysfunction and/or transformation. The median time to organ dysfunction/transformation was 29.9 months.

These adverse outcomes were significantly associated with inferior OS. The 10-year OS rate was 65.4% for patients with transformation at progression and 83.2% for those without transformation (P=0.0017).

The 10-year OS rate was 71.5% for those with organ dysfunction at progression and 82.7% for those without organ dysfunction (P=0.028).

Comparison to treated patients

The investigators also looked at a comparison group of 236 FL patients managed with immediate rituximab-based chemotherapy (R-chemo), most of whom were scheduled to receive (72.9%) rituximab maintenance. Their median age was 52.1 (range, 27.3-65.4), and most (82.6%) had advanced stage disease.

At a median follow-up of 100.2 months, the median progression-free survival (PFS) was not reached. The 10-year OS rate was 84%.

The 10-year PFS rate after first R-chemo was 57.1% for patients who received immediate R-chemo (n=236) and 50.5% for patients who were initially managed with watchful waiting and proceeded to R-chemo (n=133; P=0.506). This was not affected by rituximab maintenance.

The investigators noted that OS measured from diagnosis was not affected by initial watchful waiting.

However, in a landmark analysis, OS was inferior when measured from R-chemo at first progression for watchful waiting recipients compared to patients who received immediate R-chemo. The 10-year OS rates were 74.4% and 84.0%, respectively (P=0.02).

The risk of transformation at first progression was significantly different between the groups. At 10 years, the rate of transformation was 25.5% in the watchful waiting group and 6.3% in the immediate R-chemo group (P<0.0001).

The investigators said these findings, taken together, suggest changes may be warranted for FL patients managed with watchful waiting.

“Consideration should be given to implementing standardized follow-up imaging, with early initiation of rituximab-based therapy if there is evidence of progression in an attempt to prevent these potentially clinically impactful events [i.e., organ dysfunction and transformation],” Dr. Davies and her coauthors wrote.

Dr. Davies reported no financial disclosures. Her coauthors reported disclosures related to Janssen, Gilead Sciences, Lundbeck, Roche, AbbVie, Amgen, Seattle Genetics, Bristol-Myers Squibb, Servier Laboratories, and Merck.

A substantial proportion of patients with follicular lymphoma managed with watchful waiting develop organ dysfunction or transformation that may negatively impact survival outcomes, results of a retrospective study suggest.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

About one-quarter of patients managed with watchful waiting developed significant organ dysfunction or transformation at first progression over 8.2 years of follow-up.

Organ dysfunction and transformation were associated with significantly worse overall survival that could not be predicted based on baseline characteristics, the study authors reported in Clinical Lymphoma, Myeloma & Leukemia.

The study confirmed certain benefits of watchful waiting, including a low risk of progression and an “excellent” rate of overall survival, the investigators said.

However, the substantial rate of organ dysfunction and transformation in a subset of patients is “clinically meaningful for informed decision making,” reported Gwynivere A. Davies, MD, of the University of Calgary (Alta.), and her coauthors.

“While consenting patients to initial [watchful waiting], patients need to be informed about the risk for these adverse events, as well as receiving education and the need for close monitoring regarding symptoms that may indicate serious progression events,” Dr. Davies and her coauthors wrote.

Alternatively, rituximab chemotherapy, with or without rituximab maintenance, might be warranted for watchful waiting patients with clear disease progression before organ dysfunction or transformation events, despite not meeting high-tumor burden therapy indications.

SOURCE: Davies GA et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 28. doi: 10.1016/j.clml.2018.08.015.

A substantial proportion of patients with follicular lymphoma managed with watchful waiting develop organ dysfunction or transformation that may negatively impact survival outcomes, results of a retrospective study suggest.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

About one-quarter of patients managed with watchful waiting developed significant organ dysfunction or transformation at first progression over 8.2 years of follow-up.

Organ dysfunction and transformation were associated with significantly worse overall survival that could not be predicted based on baseline characteristics, the study authors reported in Clinical Lymphoma, Myeloma & Leukemia.

The study confirmed certain benefits of watchful waiting, including a low risk of progression and an “excellent” rate of overall survival, the investigators said.

However, the substantial rate of organ dysfunction and transformation in a subset of patients is “clinically meaningful for informed decision making,” reported Gwynivere A. Davies, MD, of the University of Calgary (Alta.), and her coauthors.

“While consenting patients to initial [watchful waiting], patients need to be informed about the risk for these adverse events, as well as receiving education and the need for close monitoring regarding symptoms that may indicate serious progression events,” Dr. Davies and her coauthors wrote.

Alternatively, rituximab chemotherapy, with or without rituximab maintenance, might be warranted for watchful waiting patients with clear disease progression before organ dysfunction or transformation events, despite not meeting high-tumor burden therapy indications.

SOURCE: Davies GA et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 28. doi: 10.1016/j.clml.2018.08.015.

A substantial proportion of patients with follicular lymphoma managed with watchful waiting develop organ dysfunction or transformation that may negatively impact survival outcomes, results of a retrospective study suggest.

Patho/Wikimedia Commons/CC BY-SA 3.0(http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

About one-quarter of patients managed with watchful waiting developed significant organ dysfunction or transformation at first progression over 8.2 years of follow-up.

Organ dysfunction and transformation were associated with significantly worse overall survival that could not be predicted based on baseline characteristics, the study authors reported in Clinical Lymphoma, Myeloma & Leukemia.

The study confirmed certain benefits of watchful waiting, including a low risk of progression and an “excellent” rate of overall survival, the investigators said.

However, the substantial rate of organ dysfunction and transformation in a subset of patients is “clinically meaningful for informed decision making,” reported Gwynivere A. Davies, MD, of the University of Calgary (Alta.), and her coauthors.

“While consenting patients to initial [watchful waiting], patients need to be informed about the risk for these adverse events, as well as receiving education and the need for close monitoring regarding symptoms that may indicate serious progression events,” Dr. Davies and her coauthors wrote.

Alternatively, rituximab chemotherapy, with or without rituximab maintenance, might be warranted for watchful waiting patients with clear disease progression before organ dysfunction or transformation events, despite not meeting high-tumor burden therapy indications.

SOURCE: Davies GA et al. Clin Lymphoma Myeloma Leuk. 2018 Aug 28. doi: 10.1016/j.clml.2018.08.015.

Health Canada has authorized use of tisagenlecleucel (Kymriah), the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval in Canada.

Tisagenlecleucel is approved to treat patients aged 3-25 years who have B-cell acute lymphoblastic leukemia (ALL) and relapsed after allogenic stem cell transplant (SCT) or are otherwise ineligible for SCT, have experienced second or later relapse, or have refractory disease.

Tisagenlecleucel is also approved in Canada to treat adults who have received two or more lines of systemic therapy and have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.

Novartis, the company marketing tisagenlecleucel, said it is working with qualified treatment centers in Canada to prepare for the delivery of tisagenlecleucel. Certification and training are underway at these centers and Novartis is enhancing manufacturing capacity to meet patient needs.

Tisagenlecleucel has been studied in a pair of phase 2 trials – JULIET and ELIANA.

JULIET enrolled 165 adults with relapsed/refractory DLBCL, 111 of whom received a single infusion of tisagenlecleucel.

The overall response rate was 52% and the complete response (CR) rate was 40%. The median duration of response was not reached with a median follow-up of 13.9 months. At last follow-up, none of the responders had gone on to SCT.

The 12-month overall survival (OS) rate was 49%; the median OS was 11.7 months. The median OS was not reached for patients in CR.

Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome.

These results were presented at the 2018 annual congress of the European Hematology Association in June.

The ELIANA trial included 75 children and young adults with relapsed/refractory ALL. All patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.

The median duration of follow-up was 13.1 months. The overall remission rate was 81%, with 60% of patients achieving a CR and 21% achieving CR with incomplete hematologic recovery. All patients whose best response was CR with incomplete hematologic recovery were negative for minimal residual disease. The median duration of response was not met.

Eight patients proceeded to SCT while in remission. At last follow-up, four were still in remission, and four had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

About 95% of patients had adverse events thought to be related to tisagenlecleucel. The incidence of treatment-related grade 3/4 adverse eventss was 73% (N Engl J Med 2018; 378:439-48).

jensmith@mdedge.com

Health Canada has authorized use of tisagenlecleucel (Kymriah), the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval in Canada.

Tisagenlecleucel is approved to treat patients aged 3-25 years who have B-cell acute lymphoblastic leukemia (ALL) and relapsed after allogenic stem cell transplant (SCT) or are otherwise ineligible for SCT, have experienced second or later relapse, or have refractory disease.

Tisagenlecleucel is also approved in Canada to treat adults who have received two or more lines of systemic therapy and have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.

Novartis, the company marketing tisagenlecleucel, said it is working with qualified treatment centers in Canada to prepare for the delivery of tisagenlecleucel. Certification and training are underway at these centers and Novartis is enhancing manufacturing capacity to meet patient needs.

Tisagenlecleucel has been studied in a pair of phase 2 trials – JULIET and ELIANA.

JULIET enrolled 165 adults with relapsed/refractory DLBCL, 111 of whom received a single infusion of tisagenlecleucel.

The overall response rate was 52% and the complete response (CR) rate was 40%. The median duration of response was not reached with a median follow-up of 13.9 months. At last follow-up, none of the responders had gone on to SCT.

The 12-month overall survival (OS) rate was 49%; the median OS was 11.7 months. The median OS was not reached for patients in CR.

Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome.

These results were presented at the 2018 annual congress of the European Hematology Association in June.

The ELIANA trial included 75 children and young adults with relapsed/refractory ALL. All patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.

The median duration of follow-up was 13.1 months. The overall remission rate was 81%, with 60% of patients achieving a CR and 21% achieving CR with incomplete hematologic recovery. All patients whose best response was CR with incomplete hematologic recovery were negative for minimal residual disease. The median duration of response was not met.

Eight patients proceeded to SCT while in remission. At last follow-up, four were still in remission, and four had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

About 95% of patients had adverse events thought to be related to tisagenlecleucel. The incidence of treatment-related grade 3/4 adverse eventss was 73% (N Engl J Med 2018; 378:439-48).

jensmith@mdedge.com

Health Canada has authorized use of tisagenlecleucel (Kymriah), the first chimeric antigen receptor (CAR) T-cell therapy to receive regulatory approval in Canada.

Tisagenlecleucel is approved to treat patients aged 3-25 years who have B-cell acute lymphoblastic leukemia (ALL) and relapsed after allogenic stem cell transplant (SCT) or are otherwise ineligible for SCT, have experienced second or later relapse, or have refractory disease.

Tisagenlecleucel is also approved in Canada to treat adults who have received two or more lines of systemic therapy and have relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, or DLBCL arising from follicular lymphoma.

Novartis, the company marketing tisagenlecleucel, said it is working with qualified treatment centers in Canada to prepare for the delivery of tisagenlecleucel. Certification and training are underway at these centers and Novartis is enhancing manufacturing capacity to meet patient needs.

Tisagenlecleucel has been studied in a pair of phase 2 trials – JULIET and ELIANA.

JULIET enrolled 165 adults with relapsed/refractory DLBCL, 111 of whom received a single infusion of tisagenlecleucel.

The overall response rate was 52% and the complete response (CR) rate was 40%. The median duration of response was not reached with a median follow-up of 13.9 months. At last follow-up, none of the responders had gone on to SCT.

The 12-month overall survival (OS) rate was 49%; the median OS was 11.7 months. The median OS was not reached for patients in CR.

Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome.

These results were presented at the 2018 annual congress of the European Hematology Association in June.

The ELIANA trial included 75 children and young adults with relapsed/refractory ALL. All patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.

The median duration of follow-up was 13.1 months. The overall remission rate was 81%, with 60% of patients achieving a CR and 21% achieving CR with incomplete hematologic recovery. All patients whose best response was CR with incomplete hematologic recovery were negative for minimal residual disease. The median duration of response was not met.

Eight patients proceeded to SCT while in remission. At last follow-up, four were still in remission, and four had unknown disease status.

At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.

About 95% of patients had adverse events thought to be related to tisagenlecleucel. The incidence of treatment-related grade 3/4 adverse eventss was 73% (N Engl J Med 2018; 378:439-48).

jensmith@mdedge.com