TBD Meeting (4845-19)

AMSTERDAM – Rozanolixizumab, a subcutaneous antibody for the human neonatal Fc receptor, provides clinically meaningful improvements in platelet count for patients with primary immune thrombocytopenia, according to results from a recent phase 2 trial.

Rozanolixizumab was well tolerated across all dose groups, with higher doses delivering faster responses, reported lead author Tadeusz Robak, MD, PhD, of the Medical University of Lodz (Poland).

Targeting the Fc receptor interrupts recirculation of IgG, a key autoantibody in immune thrombocytopenia (ITP) pathogenesis, Dr. Robak explained during a presentation at the annual congress of the European Hematology Association. This approach represents an emerging treatment paradigm, he said, noting that rozanolixizumab is also being studied for the treatment of other IgG-driven autoimmune diseases, such as myasthenia gravis and chronic inflammatory demyelinating polyneuropathy.

The present open-label, dose-escalation study involved 54 adult patients with primary ITP of at least 3 months duration and platelet counts of less than 30 x 10⁹/L at screening and 35 x 10⁹/L at baseline. Eligibility required a previous response to ITP therapy. Enrolled patients were randomized into four dose groups: 4 mg/kg (five doses), 7 mg/kg (three doses), 10 mg/kg (two doses), or 15 mg/kg (one dose). After dosing, patients were followed for 8 weeks. Clinically relevant efficacy was defined as a platelet count of at least 50 x 10⁹/L. Decreases in IgG were also reported.

A safety analysis showed that the regimen was well tolerated across all dose groups. In total, 20.4% of patients experienced at least one treatment-related adverse event. The most common adverse events were headache (31.5%), diarrhea (11.1%), and vomiting (3.7%); all of which were mild or moderate. Headache appeared to be dose related, as 42% of patients in the 15-mg/kg group reported headache, compared with 8% in the 10-mg/kg group, 7% in the 7-mg/kg group, and none in the 4-mg/kg group. Out of four reported serious adverse events, none were considered treatment related.

Concerning efficacy, higher doses were associated with higher response rates and faster response times. In the 4-mg/kg group, 33% of patients achieved a platelet count of at least 50 x 10⁹/L, compared with 33% of the 7-mg/kg group, 50% of the 10-mg/kg group, and 67% of the 15-mg/kg group. Of the patients that achieved clinically meaningful responses, 20% of the 4-mg/kg group did so within 8 days, compared with 40% of 7-mg/kg responders, 50% of 10-mg/kg responders, and 87.5% of 15-mg/kg responders. Additional observations included dose-dependent decreases in IgG titer and longer response durations after multiple lower doses.

“Data from this study indicate that we can achieve effective increases in platelet levels, we can observe decreasing IgG levels, and the treatment was safe for the patients,” Dr. Robak said.

When asked about the intended clinical application of rozanolixizumab, Dr. Robak suggested that the agent may have a role in the postacute care setting. “We should develop a method of prolonged administration of [rozanolixizumab], as we saw that lower, multiple doses gave longer response durations.”

Still, he noted that more research is needed, since responses in diverse patient populations remain unknown. “We do not know how the drug will be active in truly refractory patients and we need this response before we establish the indication for the drug.”

The investigators reported financial relationships with Celgene, Roche, GlaxoSmithKline, Amgen, AbbVie, and other companies.

SOURCE: Robak T et al. EHA Congress, Abstract S850.

AMSTERDAM – Rozanolixizumab, a subcutaneous antibody for the human neonatal Fc receptor, provides clinically meaningful improvements in platelet count for patients with primary immune thrombocytopenia, according to results from a recent phase 2 trial.

Rozanolixizumab was well tolerated across all dose groups, with higher doses delivering faster responses, reported lead author Tadeusz Robak, MD, PhD, of the Medical University of Lodz (Poland).

Targeting the Fc receptor interrupts recirculation of IgG, a key autoantibody in immune thrombocytopenia (ITP) pathogenesis, Dr. Robak explained during a presentation at the annual congress of the European Hematology Association. This approach represents an emerging treatment paradigm, he said, noting that rozanolixizumab is also being studied for the treatment of other IgG-driven autoimmune diseases, such as myasthenia gravis and chronic inflammatory demyelinating polyneuropathy.

The present open-label, dose-escalation study involved 54 adult patients with primary ITP of at least 3 months duration and platelet counts of less than 30 x 10⁹/L at screening and 35 x 10⁹/L at baseline. Eligibility required a previous response to ITP therapy. Enrolled patients were randomized into four dose groups: 4 mg/kg (five doses), 7 mg/kg (three doses), 10 mg/kg (two doses), or 15 mg/kg (one dose). After dosing, patients were followed for 8 weeks. Clinically relevant efficacy was defined as a platelet count of at least 50 x 10⁹/L. Decreases in IgG were also reported.

A safety analysis showed that the regimen was well tolerated across all dose groups. In total, 20.4% of patients experienced at least one treatment-related adverse event. The most common adverse events were headache (31.5%), diarrhea (11.1%), and vomiting (3.7%); all of which were mild or moderate. Headache appeared to be dose related, as 42% of patients in the 15-mg/kg group reported headache, compared with 8% in the 10-mg/kg group, 7% in the 7-mg/kg group, and none in the 4-mg/kg group. Out of four reported serious adverse events, none were considered treatment related.

Concerning efficacy, higher doses were associated with higher response rates and faster response times. In the 4-mg/kg group, 33% of patients achieved a platelet count of at least 50 x 10⁹/L, compared with 33% of the 7-mg/kg group, 50% of the 10-mg/kg group, and 67% of the 15-mg/kg group. Of the patients that achieved clinically meaningful responses, 20% of the 4-mg/kg group did so within 8 days, compared with 40% of 7-mg/kg responders, 50% of 10-mg/kg responders, and 87.5% of 15-mg/kg responders. Additional observations included dose-dependent decreases in IgG titer and longer response durations after multiple lower doses.

“Data from this study indicate that we can achieve effective increases in platelet levels, we can observe decreasing IgG levels, and the treatment was safe for the patients,” Dr. Robak said.

When asked about the intended clinical application of rozanolixizumab, Dr. Robak suggested that the agent may have a role in the postacute care setting. “We should develop a method of prolonged administration of [rozanolixizumab], as we saw that lower, multiple doses gave longer response durations.”

Still, he noted that more research is needed, since responses in diverse patient populations remain unknown. “We do not know how the drug will be active in truly refractory patients and we need this response before we establish the indication for the drug.”

The investigators reported financial relationships with Celgene, Roche, GlaxoSmithKline, Amgen, AbbVie, and other companies.

SOURCE: Robak T et al. EHA Congress, Abstract S850.

AMSTERDAM – Rozanolixizumab, a subcutaneous antibody for the human neonatal Fc receptor, provides clinically meaningful improvements in platelet count for patients with primary immune thrombocytopenia, according to results from a recent phase 2 trial.

Rozanolixizumab was well tolerated across all dose groups, with higher doses delivering faster responses, reported lead author Tadeusz Robak, MD, PhD, of the Medical University of Lodz (Poland).

Targeting the Fc receptor interrupts recirculation of IgG, a key autoantibody in immune thrombocytopenia (ITP) pathogenesis, Dr. Robak explained during a presentation at the annual congress of the European Hematology Association. This approach represents an emerging treatment paradigm, he said, noting that rozanolixizumab is also being studied for the treatment of other IgG-driven autoimmune diseases, such as myasthenia gravis and chronic inflammatory demyelinating polyneuropathy.

The present open-label, dose-escalation study involved 54 adult patients with primary ITP of at least 3 months duration and platelet counts of less than 30 x 10⁹/L at screening and 35 x 10⁹/L at baseline. Eligibility required a previous response to ITP therapy. Enrolled patients were randomized into four dose groups: 4 mg/kg (five doses), 7 mg/kg (three doses), 10 mg/kg (two doses), or 15 mg/kg (one dose). After dosing, patients were followed for 8 weeks. Clinically relevant efficacy was defined as a platelet count of at least 50 x 10⁹/L. Decreases in IgG were also reported.

A safety analysis showed that the regimen was well tolerated across all dose groups. In total, 20.4% of patients experienced at least one treatment-related adverse event. The most common adverse events were headache (31.5%), diarrhea (11.1%), and vomiting (3.7%); all of which were mild or moderate. Headache appeared to be dose related, as 42% of patients in the 15-mg/kg group reported headache, compared with 8% in the 10-mg/kg group, 7% in the 7-mg/kg group, and none in the 4-mg/kg group. Out of four reported serious adverse events, none were considered treatment related.

Concerning efficacy, higher doses were associated with higher response rates and faster response times. In the 4-mg/kg group, 33% of patients achieved a platelet count of at least 50 x 10⁹/L, compared with 33% of the 7-mg/kg group, 50% of the 10-mg/kg group, and 67% of the 15-mg/kg group. Of the patients that achieved clinically meaningful responses, 20% of the 4-mg/kg group did so within 8 days, compared with 40% of 7-mg/kg responders, 50% of 10-mg/kg responders, and 87.5% of 15-mg/kg responders. Additional observations included dose-dependent decreases in IgG titer and longer response durations after multiple lower doses.

“Data from this study indicate that we can achieve effective increases in platelet levels, we can observe decreasing IgG levels, and the treatment was safe for the patients,” Dr. Robak said.

When asked about the intended clinical application of rozanolixizumab, Dr. Robak suggested that the agent may have a role in the postacute care setting. “We should develop a method of prolonged administration of [rozanolixizumab], as we saw that lower, multiple doses gave longer response durations.”

Still, he noted that more research is needed, since responses in diverse patient populations remain unknown. “We do not know how the drug will be active in truly refractory patients and we need this response before we establish the indication for the drug.”

The investigators reported financial relationships with Celgene, Roche, GlaxoSmithKline, Amgen, AbbVie, and other companies.

SOURCE: Robak T et al. EHA Congress, Abstract S850.

AMSTERDAM – For patients with immune thrombocytopenia (ITP), platelet glycoprotein genotypes may predict effectiveness of specific therapies, according to investigators.

Will Pass/MDedge News

Significant relationships were detected between allelic polymorphisms of glycoprotein genes and durable responses to corticosteroids, thrombopoietin receptor agonists (aTPOr), and splenectomy, reported lead author Irina Zotova, MD, of the Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency, in Saint Petersburg and colleagues.

These findings could guide clinical decision making in ITP, according to Dr. Zotova.

“Currently, the choice of therapeutic approach to ITP treatment, especially the second-line, is empirical, and often based on the experience of the clinician,” Dr. Zotova said during her presentation at the annual congress of the European Hematology Association. “Recent studies have shown that ... genes coding for glycoprotein are involved in platelet function and are associated with different responses to ITP treatment. This provides an opportunity for an individual approach and personalization of ITP therapy in accordance with the genetic status of the patient.”

In the present study, the investigators used PCR-RFLP (polymerase chain reaction–restriction fragment length polymorphism) to determine GPIa A1648G and GPIIb 2622TG gene status in 81 patients with primary ITP and compared these genotypes with clinical responses.

All patients received first-line corticosteroid therapy. If necessary, second-line treatment was delivered. In total, 37 patients (46%) received aTPOr, while 22 patients (27%) underwent splenectomy. Responses were classified as durable response, nondurable response, or no response.

Analysis showed that a significantly greater proportion of patients who had durable responses to corticosteroid therapy exhibited a heterozygous GPIIb 2622TG genotype, compared with patients who had nondurable responses (72.2% vs. 30.9%; odds ratio, 5.8; P = .005).

For second-line responses, patients who had durable response to aTPOr were much more likely to be homozygous for the GPIa A1648G than nonresponders (87.5% vs. 20.0%; OR, 28.0; P = .005). More strikingly, all patients who achieved durable responses to splenectomy had the GPIa A1648G genotype, compared with just 44% of nonresponders (OR, 33.0; P = .005).

“Gentoyping for the GPIIb T2622G and GPIa A1648G polymorphisms allows [clinicians] to predict the response to first-line and second-line treatment, giving the possibility to stratify patients to groups with favorable and unfavorable courses of the disease,” Dr. Zotova concluded.

Will Pass/MDedge News

Session moderator János Kappelmayer, MD, of the University of Debrecen (Hungary) highlighted a key opportunity presented by the study. “I think that one important aspect of these findings could be that splenectomy is an irreversible procedure, so one can exclude those patients who will not benefit from splenectomy,” he said. “I think this is a real advantage.”

The investigators reported no study funding or conflicts of interest.

SOURCE: Zotova I et al. EHA Congress, Abstract S848.

AMSTERDAM – For patients with immune thrombocytopenia (ITP), platelet glycoprotein genotypes may predict effectiveness of specific therapies, according to investigators.

Will Pass/MDedge News

Significant relationships were detected between allelic polymorphisms of glycoprotein genes and durable responses to corticosteroids, thrombopoietin receptor agonists (aTPOr), and splenectomy, reported lead author Irina Zotova, MD, of the Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency, in Saint Petersburg and colleagues.

These findings could guide clinical decision making in ITP, according to Dr. Zotova.

“Currently, the choice of therapeutic approach to ITP treatment, especially the second-line, is empirical, and often based on the experience of the clinician,” Dr. Zotova said during her presentation at the annual congress of the European Hematology Association. “Recent studies have shown that ... genes coding for glycoprotein are involved in platelet function and are associated with different responses to ITP treatment. This provides an opportunity for an individual approach and personalization of ITP therapy in accordance with the genetic status of the patient.”

In the present study, the investigators used PCR-RFLP (polymerase chain reaction–restriction fragment length polymorphism) to determine GPIa A1648G and GPIIb 2622TG gene status in 81 patients with primary ITP and compared these genotypes with clinical responses.

All patients received first-line corticosteroid therapy. If necessary, second-line treatment was delivered. In total, 37 patients (46%) received aTPOr, while 22 patients (27%) underwent splenectomy. Responses were classified as durable response, nondurable response, or no response.

Analysis showed that a significantly greater proportion of patients who had durable responses to corticosteroid therapy exhibited a heterozygous GPIIb 2622TG genotype, compared with patients who had nondurable responses (72.2% vs. 30.9%; odds ratio, 5.8; P = .005).

For second-line responses, patients who had durable response to aTPOr were much more likely to be homozygous for the GPIa A1648G than nonresponders (87.5% vs. 20.0%; OR, 28.0; P = .005). More strikingly, all patients who achieved durable responses to splenectomy had the GPIa A1648G genotype, compared with just 44% of nonresponders (OR, 33.0; P = .005).

“Gentoyping for the GPIIb T2622G and GPIa A1648G polymorphisms allows [clinicians] to predict the response to first-line and second-line treatment, giving the possibility to stratify patients to groups with favorable and unfavorable courses of the disease,” Dr. Zotova concluded.

Will Pass/MDedge News

Session moderator János Kappelmayer, MD, of the University of Debrecen (Hungary) highlighted a key opportunity presented by the study. “I think that one important aspect of these findings could be that splenectomy is an irreversible procedure, so one can exclude those patients who will not benefit from splenectomy,” he said. “I think this is a real advantage.”

The investigators reported no study funding or conflicts of interest.

SOURCE: Zotova I et al. EHA Congress, Abstract S848.

AMSTERDAM – For patients with immune thrombocytopenia (ITP), platelet glycoprotein genotypes may predict effectiveness of specific therapies, according to investigators.

Will Pass/MDedge News

Significant relationships were detected between allelic polymorphisms of glycoprotein genes and durable responses to corticosteroids, thrombopoietin receptor agonists (aTPOr), and splenectomy, reported lead author Irina Zotova, MD, of the Russian Research Institute of Hematology and Transfusiology, Federal Biomedical Agency, in Saint Petersburg and colleagues.

These findings could guide clinical decision making in ITP, according to Dr. Zotova.

“Currently, the choice of therapeutic approach to ITP treatment, especially the second-line, is empirical, and often based on the experience of the clinician,” Dr. Zotova said during her presentation at the annual congress of the European Hematology Association. “Recent studies have shown that ... genes coding for glycoprotein are involved in platelet function and are associated with different responses to ITP treatment. This provides an opportunity for an individual approach and personalization of ITP therapy in accordance with the genetic status of the patient.”

In the present study, the investigators used PCR-RFLP (polymerase chain reaction–restriction fragment length polymorphism) to determine GPIa A1648G and GPIIb 2622TG gene status in 81 patients with primary ITP and compared these genotypes with clinical responses.

All patients received first-line corticosteroid therapy. If necessary, second-line treatment was delivered. In total, 37 patients (46%) received aTPOr, while 22 patients (27%) underwent splenectomy. Responses were classified as durable response, nondurable response, or no response.

Analysis showed that a significantly greater proportion of patients who had durable responses to corticosteroid therapy exhibited a heterozygous GPIIb 2622TG genotype, compared with patients who had nondurable responses (72.2% vs. 30.9%; odds ratio, 5.8; P = .005).

For second-line responses, patients who had durable response to aTPOr were much more likely to be homozygous for the GPIa A1648G than nonresponders (87.5% vs. 20.0%; OR, 28.0; P = .005). More strikingly, all patients who achieved durable responses to splenectomy had the GPIa A1648G genotype, compared with just 44% of nonresponders (OR, 33.0; P = .005).

“Gentoyping for the GPIIb T2622G and GPIa A1648G polymorphisms allows [clinicians] to predict the response to first-line and second-line treatment, giving the possibility to stratify patients to groups with favorable and unfavorable courses of the disease,” Dr. Zotova concluded.

Will Pass/MDedge News

Session moderator János Kappelmayer, MD, of the University of Debrecen (Hungary) highlighted a key opportunity presented by the study. “I think that one important aspect of these findings could be that splenectomy is an irreversible procedure, so one can exclude those patients who will not benefit from splenectomy,” he said. “I think this is a real advantage.”

The investigators reported no study funding or conflicts of interest.

SOURCE: Zotova I et al. EHA Congress, Abstract S848.

AMSTERDAM – The novel monoclonal antibody Hu5F9, when combined with rituximab, effectively tells macrophages that it’s okay to chow down on lymphoma cells but lay off munching on normal cells, thereby thwarting a mechanism that non-Hodgkin lymphomas (NHL) use to evade immune surveillance, investigators report.

Among 97 patients with relapsed or refractory aggressive or indolent lymphomas in a phase 1b/2 trial who were treated with Hu5F9 (5F9) plus rituximab, the objective response rate (ORR) was 45%, reported Mark Roschewski, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.

5F9 is an immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

“Rituximab, through its activity on the Fc receptor, places an extrinsic ‘eat me’ signal, so when you give these two things together you’re blocking the ‘don’t eat me’ signal and you’re placing the ‘eat me’ signal, and then the cell becomes susceptible to phagocytosis,” he said in a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

5F9 is the first agent in its class and the most advanced in clinical trials, but several similar agents are also in development. As previously reported, a similar molecule labeled TTI-621 has shown early activity in the treatment of T-cell lymphomas.

In an interview, Dr. Roschewski explained that the therapeutic approach shows promise for the treatment of NHL and nonmalignant diseases.

“This target isn’t even specific to cancer. There is rationale for using this to treat infections or other conditions. Basically, anything that your innate immune system should normally chew up, if that cell has always been evading it using that signal, this removes that [evasion] mechanism,” he said.

In preclinical studies, 5F9 showed the most activity against NHL and acute myeloid leukemia, he noted.

Results of the phase 1b portion of the study were reported in the New England Journal of Medicine (2018;379:1711-21). At the EHA Congress, Dr. Roschewski reported on extended follow-up of the phase 1b cohort and preliminary phase 2 data.

In phase 2, the investigators enrolled patients with diffuse large B-cell lymphoma (DLBCL) that was either primary refractory to standard therapy or relapsed/refractory after two or more prior lines of therapy and who were not eligible for chimeric antigen receptor T-cell therapy. They also enrolled a smaller cohort of patients with the indolent lymphoma histologies follicular lymphoma and marginal zone lymphoma (MZL) whose disease was relapsed or refractory to at least two prior lines.

Dr. Roschewski reported on pooled data for 115 patients enrolled in phases 1b and 2: 70 with DLBCL, 41 with FL, and 4 with MZL.


The patients were heavily pretreated with a median of three prior lines of therapy. Of the patients with DLBCL, 59% had primary refractory disease, and 89% of the patients with DLBCL in phase 2 were not eligible for CAR T-cell therapy.

Among all patients in this analysis, 85% had disease that was refractory to a prior rituximab-containing regimen, and the majority had disease that was refractory to the last rituximab-containing regimen.

Among 97 patients evaluable for response (59 with DLBCL, 35 with FL, and 3 with MZL), the ORR was 45%, including 19% CR and 27% partial responses (PR). An additional 17% of patients had stable disease, and 38% experienced disease progression.

The ORR for DLBCL patients was 35%, consisting of 15% CR and 20% PR. An additional 12% of patients with DLBCL had stable disease, and 53% experienced progression.

Of the patients with indolent lymphomas, the ORR was 61%, including 24% CR and 37% PR. Of this group, 24% had stable disease, and 16% had disease progression.

For all patients, the median time to response was 1.8 months (range 1.6-7.3 months).

Efficacy among patients with DLBCL was similar across subtypes and for patients with primary refractory vs. acquired refractory disease. The responses also were similar irrespective of prior lines of therapy.

Patients tolerated the combination well, with no maximum tolerated dose at up to 45 mg/kg of 5F9, and no significant dose-related toxicities.

Most adverse events were grade 1 or 2. The most common adverse events included expected on-target anemia, caused by clearance of aging red blood cells, which are cleared by the CD47-blocking effects of 5F9. This anemia can be mitigated with an initial priming dose of 1 mg/kg 5FP that causes a transient mild decline in hemoglobin and a temporary reticulocytosis that soon resolves. Hemoglobin levels return to baseline even with continued 5F9 at doses much higher than the priming dose, Dr. Roschewski said.

Other adverse events were infusion reactions and related symptoms. There were no autoimmune adverse events, and just 8 of the 115 patients available for the safety analysis (7%) had to discontinue therapy.

Enrollment in the phase 2 trial is continuing, and a 30-mg/kg maintenance dose of 5F9 has been selected for a trial in patients with DLBCL who are either ineligible for CAR T-cell therapy or have disease that progressed on three or more prior lines of therapy.

The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.

SOURCE: Roschewski M et al. EHA Congress, Abstract S867.

AMSTERDAM – The novel monoclonal antibody Hu5F9, when combined with rituximab, effectively tells macrophages that it’s okay to chow down on lymphoma cells but lay off munching on normal cells, thereby thwarting a mechanism that non-Hodgkin lymphomas (NHL) use to evade immune surveillance, investigators report.

Among 97 patients with relapsed or refractory aggressive or indolent lymphomas in a phase 1b/2 trial who were treated with Hu5F9 (5F9) plus rituximab, the objective response rate (ORR) was 45%, reported Mark Roschewski, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.

5F9 is an immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

“Rituximab, through its activity on the Fc receptor, places an extrinsic ‘eat me’ signal, so when you give these two things together you’re blocking the ‘don’t eat me’ signal and you’re placing the ‘eat me’ signal, and then the cell becomes susceptible to phagocytosis,” he said in a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

5F9 is the first agent in its class and the most advanced in clinical trials, but several similar agents are also in development. As previously reported, a similar molecule labeled TTI-621 has shown early activity in the treatment of T-cell lymphomas.

In an interview, Dr. Roschewski explained that the therapeutic approach shows promise for the treatment of NHL and nonmalignant diseases.

“This target isn’t even specific to cancer. There is rationale for using this to treat infections or other conditions. Basically, anything that your innate immune system should normally chew up, if that cell has always been evading it using that signal, this removes that [evasion] mechanism,” he said.

In preclinical studies, 5F9 showed the most activity against NHL and acute myeloid leukemia, he noted.

Results of the phase 1b portion of the study were reported in the New England Journal of Medicine (2018;379:1711-21). At the EHA Congress, Dr. Roschewski reported on extended follow-up of the phase 1b cohort and preliminary phase 2 data.

In phase 2, the investigators enrolled patients with diffuse large B-cell lymphoma (DLBCL) that was either primary refractory to standard therapy or relapsed/refractory after two or more prior lines of therapy and who were not eligible for chimeric antigen receptor T-cell therapy. They also enrolled a smaller cohort of patients with the indolent lymphoma histologies follicular lymphoma and marginal zone lymphoma (MZL) whose disease was relapsed or refractory to at least two prior lines.

Dr. Roschewski reported on pooled data for 115 patients enrolled in phases 1b and 2: 70 with DLBCL, 41 with FL, and 4 with MZL.


The patients were heavily pretreated with a median of three prior lines of therapy. Of the patients with DLBCL, 59% had primary refractory disease, and 89% of the patients with DLBCL in phase 2 were not eligible for CAR T-cell therapy.

Among all patients in this analysis, 85% had disease that was refractory to a prior rituximab-containing regimen, and the majority had disease that was refractory to the last rituximab-containing regimen.

Among 97 patients evaluable for response (59 with DLBCL, 35 with FL, and 3 with MZL), the ORR was 45%, including 19% CR and 27% partial responses (PR). An additional 17% of patients had stable disease, and 38% experienced disease progression.

The ORR for DLBCL patients was 35%, consisting of 15% CR and 20% PR. An additional 12% of patients with DLBCL had stable disease, and 53% experienced progression.

Of the patients with indolent lymphomas, the ORR was 61%, including 24% CR and 37% PR. Of this group, 24% had stable disease, and 16% had disease progression.

For all patients, the median time to response was 1.8 months (range 1.6-7.3 months).

Efficacy among patients with DLBCL was similar across subtypes and for patients with primary refractory vs. acquired refractory disease. The responses also were similar irrespective of prior lines of therapy.

Patients tolerated the combination well, with no maximum tolerated dose at up to 45 mg/kg of 5F9, and no significant dose-related toxicities.

Most adverse events were grade 1 or 2. The most common adverse events included expected on-target anemia, caused by clearance of aging red blood cells, which are cleared by the CD47-blocking effects of 5F9. This anemia can be mitigated with an initial priming dose of 1 mg/kg 5FP that causes a transient mild decline in hemoglobin and a temporary reticulocytosis that soon resolves. Hemoglobin levels return to baseline even with continued 5F9 at doses much higher than the priming dose, Dr. Roschewski said.

Other adverse events were infusion reactions and related symptoms. There were no autoimmune adverse events, and just 8 of the 115 patients available for the safety analysis (7%) had to discontinue therapy.

Enrollment in the phase 2 trial is continuing, and a 30-mg/kg maintenance dose of 5F9 has been selected for a trial in patients with DLBCL who are either ineligible for CAR T-cell therapy or have disease that progressed on three or more prior lines of therapy.

The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.

SOURCE: Roschewski M et al. EHA Congress, Abstract S867.

AMSTERDAM – The novel monoclonal antibody Hu5F9, when combined with rituximab, effectively tells macrophages that it’s okay to chow down on lymphoma cells but lay off munching on normal cells, thereby thwarting a mechanism that non-Hodgkin lymphomas (NHL) use to evade immune surveillance, investigators report.

Among 97 patients with relapsed or refractory aggressive or indolent lymphomas in a phase 1b/2 trial who were treated with Hu5F9 (5F9) plus rituximab, the objective response rate (ORR) was 45%, reported Mark Roschewski, MD, of the National Cancer Institute’s Center for Cancer Research in Bethesda, Md.

5F9 is an immune checkpoint inhibitor that targets CD47, the “don’t eat me” signal that inhibits macrophages from carrying out their crucial phagocytosis role.

“Rituximab, through its activity on the Fc receptor, places an extrinsic ‘eat me’ signal, so when you give these two things together you’re blocking the ‘don’t eat me’ signal and you’re placing the ‘eat me’ signal, and then the cell becomes susceptible to phagocytosis,” he said in a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

5F9 is the first agent in its class and the most advanced in clinical trials, but several similar agents are also in development. As previously reported, a similar molecule labeled TTI-621 has shown early activity in the treatment of T-cell lymphomas.

In an interview, Dr. Roschewski explained that the therapeutic approach shows promise for the treatment of NHL and nonmalignant diseases.

“This target isn’t even specific to cancer. There is rationale for using this to treat infections or other conditions. Basically, anything that your innate immune system should normally chew up, if that cell has always been evading it using that signal, this removes that [evasion] mechanism,” he said.

In preclinical studies, 5F9 showed the most activity against NHL and acute myeloid leukemia, he noted.

Results of the phase 1b portion of the study were reported in the New England Journal of Medicine (2018;379:1711-21). At the EHA Congress, Dr. Roschewski reported on extended follow-up of the phase 1b cohort and preliminary phase 2 data.

In phase 2, the investigators enrolled patients with diffuse large B-cell lymphoma (DLBCL) that was either primary refractory to standard therapy or relapsed/refractory after two or more prior lines of therapy and who were not eligible for chimeric antigen receptor T-cell therapy. They also enrolled a smaller cohort of patients with the indolent lymphoma histologies follicular lymphoma and marginal zone lymphoma (MZL) whose disease was relapsed or refractory to at least two prior lines.

Dr. Roschewski reported on pooled data for 115 patients enrolled in phases 1b and 2: 70 with DLBCL, 41 with FL, and 4 with MZL.


The patients were heavily pretreated with a median of three prior lines of therapy. Of the patients with DLBCL, 59% had primary refractory disease, and 89% of the patients with DLBCL in phase 2 were not eligible for CAR T-cell therapy.

Among all patients in this analysis, 85% had disease that was refractory to a prior rituximab-containing regimen, and the majority had disease that was refractory to the last rituximab-containing regimen.

Among 97 patients evaluable for response (59 with DLBCL, 35 with FL, and 3 with MZL), the ORR was 45%, including 19% CR and 27% partial responses (PR). An additional 17% of patients had stable disease, and 38% experienced disease progression.

The ORR for DLBCL patients was 35%, consisting of 15% CR and 20% PR. An additional 12% of patients with DLBCL had stable disease, and 53% experienced progression.

Of the patients with indolent lymphomas, the ORR was 61%, including 24% CR and 37% PR. Of this group, 24% had stable disease, and 16% had disease progression.

For all patients, the median time to response was 1.8 months (range 1.6-7.3 months).

Efficacy among patients with DLBCL was similar across subtypes and for patients with primary refractory vs. acquired refractory disease. The responses also were similar irrespective of prior lines of therapy.

Patients tolerated the combination well, with no maximum tolerated dose at up to 45 mg/kg of 5F9, and no significant dose-related toxicities.

Most adverse events were grade 1 or 2. The most common adverse events included expected on-target anemia, caused by clearance of aging red blood cells, which are cleared by the CD47-blocking effects of 5F9. This anemia can be mitigated with an initial priming dose of 1 mg/kg 5FP that causes a transient mild decline in hemoglobin and a temporary reticulocytosis that soon resolves. Hemoglobin levels return to baseline even with continued 5F9 at doses much higher than the priming dose, Dr. Roschewski said.

Other adverse events were infusion reactions and related symptoms. There were no autoimmune adverse events, and just 8 of the 115 patients available for the safety analysis (7%) had to discontinue therapy.

Enrollment in the phase 2 trial is continuing, and a 30-mg/kg maintenance dose of 5F9 has been selected for a trial in patients with DLBCL who are either ineligible for CAR T-cell therapy or have disease that progressed on three or more prior lines of therapy.

The study is funded by Forty Seven and the Leukemia and Lymphoma Society. Dr. Roschewski reported having no financial disclosures.

SOURCE: Roschewski M et al. EHA Congress, Abstract S867.

AMSTERDAM – For patients with low-risk myelodysplastic syndrome (MDS) for whom erythropoietin therapy has failed, the novel telomerase inhibitor imetelstat may provide long-lasting independence from transfusion, investigators reported.

Neil Osterweil/MDedge News

Among 38 patients with low-risk MDS who had relapsed or were refractory to treatment with an erythropoiesis stimulating agent (ESA) who received imetelstat, 16 (42%) were free from the need for transfusion for at least 8 weeks, with one patient being transfusion free for up to 141 weeks, reported Pierre Fenaux, MD, of Hôpital Saint-Louis in Paris.

Patients with a generally worse prognosis “tended to respond better to imetelstat in terms of transfusion independence, which suggests that the drug is promising for higher-risk MDS,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

Imetelstat is a first-in-class telomerase inhibitor targeting cells with short telomere lengths and active telomerase, the enzyme that maintains telomere length. Higher telomerase activity and shorter telomeres are predictive of shorter overall survival in patients with MDS, Dr. Fenaux explained.

He and colleagues enrolled 38 patients, median age 71.5 years, with low-risk MDS, with an International Prognostic Scoring System (IPSS) score of low or intermediate-1, whose disease was relapsed or refractory to ESA or to erythropoietin at a dose of more than 500 mU/mL. Of this group, 24 patients had IPSS low disease, 14 had intermediate-1 disease.

The median transfusion burden was 8 units per 8 weeks (range 4-14). The majority of patients (34, or 89%) had received prior ESAs.

The patients were transfusion dependent, defined as the need for 4 or more units of red blood cells within 8 weeks over the 16 weeks prior to study entry.

No patients had the 5q deletion, and no patients had received either a hypomethylating agent or lenolidamide (Revlimid), neither of which are approved for this indication in Europe.

The patients received imetelstat 7.5 mg/kg intravenously every 4 weeks.

As noted earlier, 16 patients (42%) achieved the primary endpoint of 8-week transfusion independence, with a median duration of 85.9 weeks (range 8-141 weeks).

Eleven patients (29%) had transfusion independence lasting at least 24 weeks – a secondary endpoint – and 26 (68%) met International Working Group 2006 criteria for a HI-E (erythroid) response, with 12 of these patients having an increase in hemoglobin of 1.5 g/dL or greater lasting for at least 8 weeks, and all 26 having a reduction in transfusions of 4 or more units over 8 weeks.

There was evidence to suggest a disease-modifying effect of imetelstat, with five patients achieving a complete response (CR), and five having a marrow CR.

The most frequent adverse events were manageable and reversible grade 3 or greater cytopenias, but there were no new safety signals seen. Two patients were hospitalized for febrile neutropenia, but there were no treatment-related deaths.

Based on these results, investigators are planning a phase 3 study comparing imetelstat with placebo in a 2:1 ratio. The trial is scheduled to begin in the late summer or fall of 2019.

When asked if imetelstat might have off-target effects by inhibiting telomerase in other cells, Dr. Fenaux replied that the mechanism of action is unclear, and that its potential effects on erythropoiesis are still unknown.

Neil Osterweil/MDedge News

Briefing moderator Anton Hagenbeek, MD, of Amsterdam University Medical Center, commented on the drug’s potential for treating MDS, and asked whether investigators are considering combining it with other therapies for MDS.

“I think the first step will be to study it in high-risk MDS as a single agent before combining it, including with hypomethylating agents, et cetera,” Dr. Fenaux replied.

SOURCE: Fenaux P et al. EHA 2019, Abstract S837.

AMSTERDAM – For patients with low-risk myelodysplastic syndrome (MDS) for whom erythropoietin therapy has failed, the novel telomerase inhibitor imetelstat may provide long-lasting independence from transfusion, investigators reported.

Neil Osterweil/MDedge News

Among 38 patients with low-risk MDS who had relapsed or were refractory to treatment with an erythropoiesis stimulating agent (ESA) who received imetelstat, 16 (42%) were free from the need for transfusion for at least 8 weeks, with one patient being transfusion free for up to 141 weeks, reported Pierre Fenaux, MD, of Hôpital Saint-Louis in Paris.

Patients with a generally worse prognosis “tended to respond better to imetelstat in terms of transfusion independence, which suggests that the drug is promising for higher-risk MDS,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

Imetelstat is a first-in-class telomerase inhibitor targeting cells with short telomere lengths and active telomerase, the enzyme that maintains telomere length. Higher telomerase activity and shorter telomeres are predictive of shorter overall survival in patients with MDS, Dr. Fenaux explained.

He and colleagues enrolled 38 patients, median age 71.5 years, with low-risk MDS, with an International Prognostic Scoring System (IPSS) score of low or intermediate-1, whose disease was relapsed or refractory to ESA or to erythropoietin at a dose of more than 500 mU/mL. Of this group, 24 patients had IPSS low disease, 14 had intermediate-1 disease.

The median transfusion burden was 8 units per 8 weeks (range 4-14). The majority of patients (34, or 89%) had received prior ESAs.

The patients were transfusion dependent, defined as the need for 4 or more units of red blood cells within 8 weeks over the 16 weeks prior to study entry.

No patients had the 5q deletion, and no patients had received either a hypomethylating agent or lenolidamide (Revlimid), neither of which are approved for this indication in Europe.

The patients received imetelstat 7.5 mg/kg intravenously every 4 weeks.

As noted earlier, 16 patients (42%) achieved the primary endpoint of 8-week transfusion independence, with a median duration of 85.9 weeks (range 8-141 weeks).

Eleven patients (29%) had transfusion independence lasting at least 24 weeks – a secondary endpoint – and 26 (68%) met International Working Group 2006 criteria for a HI-E (erythroid) response, with 12 of these patients having an increase in hemoglobin of 1.5 g/dL or greater lasting for at least 8 weeks, and all 26 having a reduction in transfusions of 4 or more units over 8 weeks.

There was evidence to suggest a disease-modifying effect of imetelstat, with five patients achieving a complete response (CR), and five having a marrow CR.

The most frequent adverse events were manageable and reversible grade 3 or greater cytopenias, but there were no new safety signals seen. Two patients were hospitalized for febrile neutropenia, but there were no treatment-related deaths.

Based on these results, investigators are planning a phase 3 study comparing imetelstat with placebo in a 2:1 ratio. The trial is scheduled to begin in the late summer or fall of 2019.

When asked if imetelstat might have off-target effects by inhibiting telomerase in other cells, Dr. Fenaux replied that the mechanism of action is unclear, and that its potential effects on erythropoiesis are still unknown.

Neil Osterweil/MDedge News

Briefing moderator Anton Hagenbeek, MD, of Amsterdam University Medical Center, commented on the drug’s potential for treating MDS, and asked whether investigators are considering combining it with other therapies for MDS.

“I think the first step will be to study it in high-risk MDS as a single agent before combining it, including with hypomethylating agents, et cetera,” Dr. Fenaux replied.

SOURCE: Fenaux P et al. EHA 2019, Abstract S837.

AMSTERDAM – For patients with low-risk myelodysplastic syndrome (MDS) for whom erythropoietin therapy has failed, the novel telomerase inhibitor imetelstat may provide long-lasting independence from transfusion, investigators reported.

Neil Osterweil/MDedge News

Among 38 patients with low-risk MDS who had relapsed or were refractory to treatment with an erythropoiesis stimulating agent (ESA) who received imetelstat, 16 (42%) were free from the need for transfusion for at least 8 weeks, with one patient being transfusion free for up to 141 weeks, reported Pierre Fenaux, MD, of Hôpital Saint-Louis in Paris.

Patients with a generally worse prognosis “tended to respond better to imetelstat in terms of transfusion independence, which suggests that the drug is promising for higher-risk MDS,” he said at a briefing prior to his presentation of the data at the annual congress of the European Hematology Association.

Imetelstat is a first-in-class telomerase inhibitor targeting cells with short telomere lengths and active telomerase, the enzyme that maintains telomere length. Higher telomerase activity and shorter telomeres are predictive of shorter overall survival in patients with MDS, Dr. Fenaux explained.

He and colleagues enrolled 38 patients, median age 71.5 years, with low-risk MDS, with an International Prognostic Scoring System (IPSS) score of low or intermediate-1, whose disease was relapsed or refractory to ESA or to erythropoietin at a dose of more than 500 mU/mL. Of this group, 24 patients had IPSS low disease, 14 had intermediate-1 disease.

The median transfusion burden was 8 units per 8 weeks (range 4-14). The majority of patients (34, or 89%) had received prior ESAs.

The patients were transfusion dependent, defined as the need for 4 or more units of red blood cells within 8 weeks over the 16 weeks prior to study entry.

No patients had the 5q deletion, and no patients had received either a hypomethylating agent or lenolidamide (Revlimid), neither of which are approved for this indication in Europe.

The patients received imetelstat 7.5 mg/kg intravenously every 4 weeks.

As noted earlier, 16 patients (42%) achieved the primary endpoint of 8-week transfusion independence, with a median duration of 85.9 weeks (range 8-141 weeks).

Eleven patients (29%) had transfusion independence lasting at least 24 weeks – a secondary endpoint – and 26 (68%) met International Working Group 2006 criteria for a HI-E (erythroid) response, with 12 of these patients having an increase in hemoglobin of 1.5 g/dL or greater lasting for at least 8 weeks, and all 26 having a reduction in transfusions of 4 or more units over 8 weeks.

There was evidence to suggest a disease-modifying effect of imetelstat, with five patients achieving a complete response (CR), and five having a marrow CR.

The most frequent adverse events were manageable and reversible grade 3 or greater cytopenias, but there were no new safety signals seen. Two patients were hospitalized for febrile neutropenia, but there were no treatment-related deaths.

Based on these results, investigators are planning a phase 3 study comparing imetelstat with placebo in a 2:1 ratio. The trial is scheduled to begin in the late summer or fall of 2019.

When asked if imetelstat might have off-target effects by inhibiting telomerase in other cells, Dr. Fenaux replied that the mechanism of action is unclear, and that its potential effects on erythropoiesis are still unknown.

Neil Osterweil/MDedge News

Briefing moderator Anton Hagenbeek, MD, of Amsterdam University Medical Center, commented on the drug’s potential for treating MDS, and asked whether investigators are considering combining it with other therapies for MDS.

“I think the first step will be to study it in high-risk MDS as a single agent before combining it, including with hypomethylating agents, et cetera,” Dr. Fenaux replied.

SOURCE: Fenaux P et al. EHA 2019, Abstract S837.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

AMSTERDAM – The investigational oral agent voxelotor induced rapid and sustained improvements in hemoglobin and hemolysis in both children and adults with sickle cell disease (SCD), follow-up results from the phase 3 HOPE trial show.

Neil Osterweil/MDedge News

Among 274 patients aged 12-59 years, those who were randomly assigned to receive voxelotor at a dose of 1,500 mg daily had significantly better hemoglobin responses – defined as an increase of more than 1.0 g/dL from baseline – than did patients assigned to placebo, reported Jo Howard, MD, of Guy’s and St. Thomas’ NHS Foundation Trust and King’s College in London.

“Voxelotor improves hemoglobin and reduces hemolysis in patients with sickle cell disease. This has the potential to reduce the morbidity in sickle cell disease and to improve the life of our patients,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.

There were no new safety signals and patients tolerated voxelotor well, she added.

The study was published simultaneously in the New England Journal of Medicine.

Voxelotor is a novel oral agent that increases hemoglobin’s affinity for oxygen by inhibiting hemoglobin polymerization and sickling of red blood cells, which if unchecked lead to serious consequences, such as chronic anemia and hemolysis, and subsequent organ damage, vaso-occlusion, stroke, or premature death.

In the HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) trial, investigators enrolled 274 adolescents and adults with SCD and randomized them on a 1:1:1 basis to receive voxelotor at doses of either 1,500 mg or 900 mg daily, or placebo.

Approximately two-thirds of the patients were receiving hydroxyurea at baseline.

In a per-protocol analysis, 59.5% of patients who received the 1,500-mg dose of voxelotor had a hemoglobin response (P less than .001 compared with baseline), as did 38% of patients in the 900-mg group (P less than .001). Among patients assigned to placebo, however, just 9.2% had a hemoglobin response, a difference that was not statistically significant.

In an intention-to-treat analysis, in which patients who did not complete the study were considered to be nonresponders, the respective rates of hemoglobin response were 51.1%, 32.6%, and 6.5%.

The difference between the 1,500-mg dose and placebo was significant (P less than .001). The difference between the 900-mg group and placebo was not statistically significant.

Hemoglobin levels of 10 g/dL or higher at week 24 were seen in 41% of the participants in the 1,500-mg group, 20% in the 900-mg group, and 9% in the placebo group.

Patients on voxelotor had an improvement in hemoglobin, whether or not they were on hydroxyurea, and those with hemoglobin either below or above 7 g/dL at baseline all had an increase in hemoglobin.

The annualized adjusted incidence rate of vaso-occlusive crises was similar in the two voxelotor groups (2.77 for the 1,500-mg dose and 2.76 for the 900-mg group) – both lower than in the placebo group (3.19).

Among patients who had two or more vaso-occlusive crises within the previous year, the respective annualized incidence rates were 2.88, 3.39, and 3.50.

There was a trend toward reduced incidence of crises with voxelotor over time, Dr. Howard said.

Grade 3 or greater adverse events occurred in 26% of patients in the 1,500-mg group, 23% in the 900-mg group, and 26% in the placebo group. The most common adverse events were headache and diarrhea.

“The data presented support the achievement of the stated primary endpoint in the HOPE trial, which was to reduce anemia and hemolysis. The hemoglobin response and reduction in hemolysis observed with an orally administered, once-daily medication with side effects that minimally affect lifestyle may make voxelotor a promising advancement in the management of sickle cell disease if approved by the [Food and Drug Administration],” Alexis Thompson, MD, MPH, of Northwestern University, Chicago, noted in an editorial accompanying the study in the New England Journal of Medicine.

Global Blood Therapeutics funded the study. Dr. Howard reported consultant/advisory board activity for the company. Dr. Thompson reported grants and/or personal fees from other companies.

SOURCE: Vichinsky E et al. EHA Congress, Abstract S147. N Engl J Med. 2019 Jun 14. doi: 10.1056/NEJMoa1903212.

AMSTERDAM – The investigational oral agent voxelotor induced rapid and sustained improvements in hemoglobin and hemolysis in both children and adults with sickle cell disease (SCD), follow-up results from the phase 3 HOPE trial show.

Neil Osterweil/MDedge News

Among 274 patients aged 12-59 years, those who were randomly assigned to receive voxelotor at a dose of 1,500 mg daily had significantly better hemoglobin responses – defined as an increase of more than 1.0 g/dL from baseline – than did patients assigned to placebo, reported Jo Howard, MD, of Guy’s and St. Thomas’ NHS Foundation Trust and King’s College in London.

“Voxelotor improves hemoglobin and reduces hemolysis in patients with sickle cell disease. This has the potential to reduce the morbidity in sickle cell disease and to improve the life of our patients,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.

There were no new safety signals and patients tolerated voxelotor well, she added.

The study was published simultaneously in the New England Journal of Medicine.

Voxelotor is a novel oral agent that increases hemoglobin’s affinity for oxygen by inhibiting hemoglobin polymerization and sickling of red blood cells, which if unchecked lead to serious consequences, such as chronic anemia and hemolysis, and subsequent organ damage, vaso-occlusion, stroke, or premature death.

In the HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) trial, investigators enrolled 274 adolescents and adults with SCD and randomized them on a 1:1:1 basis to receive voxelotor at doses of either 1,500 mg or 900 mg daily, or placebo.

Approximately two-thirds of the patients were receiving hydroxyurea at baseline.

In a per-protocol analysis, 59.5% of patients who received the 1,500-mg dose of voxelotor had a hemoglobin response (P less than .001 compared with baseline), as did 38% of patients in the 900-mg group (P less than .001). Among patients assigned to placebo, however, just 9.2% had a hemoglobin response, a difference that was not statistically significant.

In an intention-to-treat analysis, in which patients who did not complete the study were considered to be nonresponders, the respective rates of hemoglobin response were 51.1%, 32.6%, and 6.5%.

The difference between the 1,500-mg dose and placebo was significant (P less than .001). The difference between the 900-mg group and placebo was not statistically significant.

Hemoglobin levels of 10 g/dL or higher at week 24 were seen in 41% of the participants in the 1,500-mg group, 20% in the 900-mg group, and 9% in the placebo group.

Patients on voxelotor had an improvement in hemoglobin, whether or not they were on hydroxyurea, and those with hemoglobin either below or above 7 g/dL at baseline all had an increase in hemoglobin.

The annualized adjusted incidence rate of vaso-occlusive crises was similar in the two voxelotor groups (2.77 for the 1,500-mg dose and 2.76 for the 900-mg group) – both lower than in the placebo group (3.19).

Among patients who had two or more vaso-occlusive crises within the previous year, the respective annualized incidence rates were 2.88, 3.39, and 3.50.

There was a trend toward reduced incidence of crises with voxelotor over time, Dr. Howard said.

Grade 3 or greater adverse events occurred in 26% of patients in the 1,500-mg group, 23% in the 900-mg group, and 26% in the placebo group. The most common adverse events were headache and diarrhea.

“The data presented support the achievement of the stated primary endpoint in the HOPE trial, which was to reduce anemia and hemolysis. The hemoglobin response and reduction in hemolysis observed with an orally administered, once-daily medication with side effects that minimally affect lifestyle may make voxelotor a promising advancement in the management of sickle cell disease if approved by the [Food and Drug Administration],” Alexis Thompson, MD, MPH, of Northwestern University, Chicago, noted in an editorial accompanying the study in the New England Journal of Medicine.

Global Blood Therapeutics funded the study. Dr. Howard reported consultant/advisory board activity for the company. Dr. Thompson reported grants and/or personal fees from other companies.

SOURCE: Vichinsky E et al. EHA Congress, Abstract S147. N Engl J Med. 2019 Jun 14. doi: 10.1056/NEJMoa1903212.

AMSTERDAM – The investigational oral agent voxelotor induced rapid and sustained improvements in hemoglobin and hemolysis in both children and adults with sickle cell disease (SCD), follow-up results from the phase 3 HOPE trial show.

Neil Osterweil/MDedge News

Among 274 patients aged 12-59 years, those who were randomly assigned to receive voxelotor at a dose of 1,500 mg daily had significantly better hemoglobin responses – defined as an increase of more than 1.0 g/dL from baseline – than did patients assigned to placebo, reported Jo Howard, MD, of Guy’s and St. Thomas’ NHS Foundation Trust and King’s College in London.

“Voxelotor improves hemoglobin and reduces hemolysis in patients with sickle cell disease. This has the potential to reduce the morbidity in sickle cell disease and to improve the life of our patients,” she said at a briefing prior to her presentation of the data at the annual congress of the European Hematology Association.

There were no new safety signals and patients tolerated voxelotor well, she added.

The study was published simultaneously in the New England Journal of Medicine.

Voxelotor is a novel oral agent that increases hemoglobin’s affinity for oxygen by inhibiting hemoglobin polymerization and sickling of red blood cells, which if unchecked lead to serious consequences, such as chronic anemia and hemolysis, and subsequent organ damage, vaso-occlusion, stroke, or premature death.

In the HOPE (Hemoglobin Oxygen Affinity Modulation to Inhibit HbS Polymerization) trial, investigators enrolled 274 adolescents and adults with SCD and randomized them on a 1:1:1 basis to receive voxelotor at doses of either 1,500 mg or 900 mg daily, or placebo.

Approximately two-thirds of the patients were receiving hydroxyurea at baseline.

In a per-protocol analysis, 59.5% of patients who received the 1,500-mg dose of voxelotor had a hemoglobin response (P less than .001 compared with baseline), as did 38% of patients in the 900-mg group (P less than .001). Among patients assigned to placebo, however, just 9.2% had a hemoglobin response, a difference that was not statistically significant.

In an intention-to-treat analysis, in which patients who did not complete the study were considered to be nonresponders, the respective rates of hemoglobin response were 51.1%, 32.6%, and 6.5%.

The difference between the 1,500-mg dose and placebo was significant (P less than .001). The difference between the 900-mg group and placebo was not statistically significant.

Hemoglobin levels of 10 g/dL or higher at week 24 were seen in 41% of the participants in the 1,500-mg group, 20% in the 900-mg group, and 9% in the placebo group.

Patients on voxelotor had an improvement in hemoglobin, whether or not they were on hydroxyurea, and those with hemoglobin either below or above 7 g/dL at baseline all had an increase in hemoglobin.

The annualized adjusted incidence rate of vaso-occlusive crises was similar in the two voxelotor groups (2.77 for the 1,500-mg dose and 2.76 for the 900-mg group) – both lower than in the placebo group (3.19).

Among patients who had two or more vaso-occlusive crises within the previous year, the respective annualized incidence rates were 2.88, 3.39, and 3.50.

There was a trend toward reduced incidence of crises with voxelotor over time, Dr. Howard said.

Grade 3 or greater adverse events occurred in 26% of patients in the 1,500-mg group, 23% in the 900-mg group, and 26% in the placebo group. The most common adverse events were headache and diarrhea.

“The data presented support the achievement of the stated primary endpoint in the HOPE trial, which was to reduce anemia and hemolysis. The hemoglobin response and reduction in hemolysis observed with an orally administered, once-daily medication with side effects that minimally affect lifestyle may make voxelotor a promising advancement in the management of sickle cell disease if approved by the [Food and Drug Administration],” Alexis Thompson, MD, MPH, of Northwestern University, Chicago, noted in an editorial accompanying the study in the New England Journal of Medicine.

Global Blood Therapeutics funded the study. Dr. Howard reported consultant/advisory board activity for the company. Dr. Thompson reported grants and/or personal fees from other companies.

SOURCE: Vichinsky E et al. EHA Congress, Abstract S147. N Engl J Med. 2019 Jun 14. doi: 10.1056/NEJMoa1903212.