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In this edition of “How I Will Treat My Next Patient,” I highlight two recent drug approvals by the Food and Drug Administration – crizanlizumab for sickle cell patients with painful crises and zanubrutinib for mantle cell lymphoma (MCL) patients in relapse.
Crizanlizumab
P-selectin is an adhesion molecule expressed on activated vascular endothelial cells and platelets. It is a key molecule in the initiation of leukocyte rolling on vessel walls and promotes firm attachment and extravasation to underlying tissues during inflammation. Up-regulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interactions involved in the pathogenesis of sickle cell pain crises.
The SUSTAIN study was a multisite, placebo-controlled, randomized phase 2 trial of two different dosage levels of intravenous crizanlizumab (2.5 mg/kg or 5 mg/kg for 52 weeks), a humanized anti–P-selectin antibody, examining its effect on pain crises in patients with sickle cell disease. The primary endpoint was the annual rate of sickle cell pain crises, with a variety of clinically relevant secondary endpoints. The target population had 2-10 pain crises in the 12 months before enrollment. Patients on a stable dose of hydroxyurea for at least the most recent 3 months were allowed to enter, but if patients were not receiving hydroxyurea, it could not be initiated during the trial. Patients who were undergoing chronic red-cell transfusion therapy were excluded.
Among 198 enrolled patients, 35% did not complete the 52 weeks of treatment. Discontinuations were equally balanced among patients assigned to the high-dose, low-dose, and placebo cohorts. Adverse events associated with crizanlizumab included back pain, nausea, pyrexia, and arthralgia. Serious adverse events occurred in 55 patients, with 5 deaths, all of which were unrelated to treatment. Crizanlizumab did not augment hemolysis or bacterial infections.
In the efficacy analysis, patients receiving high-dose crizanlizumab had a median annual rate of 1.63 health care visits for sickle cell pain crises, compared with 2.98 visits for placebo patients (P = .01). In comparison with placebo, high-dose crizanlizumab also delayed the first pain crisis after starting treatment (4.1 months vs. 1.4 months), delayed the median time to a second pain crisis, and decreased the median number of pain crises annually.
More than twice as many high-dose crizanlizumab patients had no pain crisis episodes, compared with placebo patients. In general, differences were more striking in patients who were not taking hydroxyurea and who had non–hemoglobin SS disease. Differences in the primary endpoint between low-dose crizanlizumab and placebo were numerically, but not statistically, different.
How these results influence practice
It has been over 20 years since a new agent (hydroxyurea) was approved for sickle cell patients and, despite its use, sickle cell pain crises remain a frequent problem. Pain crises are associated with worse quality of life and increased risk of death. A promising advance is badly needed, especially in an era in which sensitivity to providers’ role in the opioid addiction crisis is highly scrutinized and may contribute to future undertreatment of pain episodes. This is especially true for patients from areas with high levels of opioid misuse.
The SUSTAIN trial was international, multi-institutional, placebo-controlled, and inclusive. These attributes enhance the likelihood that crizanlizumab will enhance patient care in routine practice. As an intravenous agent, monitoring adherence and toxicity are less challenging than with hydroxyurea. Despite these factors, however, there are some concerns. Crizanlizumab was not free of toxicity, quality of life via the Brief Pain Inventory used in the trial was not improved, and changes in the pain-severity and pain-interference domains were small. Treatment in SUSTAIN ensued for 52 weeks, so the emergence of late neutralizing antibodies and late toxicities with longer-term therapy will require careful postmarketing assessment.
These concerns notwithstanding, anyone who has cared for sickle cell patients would be excited about the potential benefits crizanlizumab could bring to patient care.
Zanubrutinib
The FDA has approved zanubrutinib for the treatment of MCL in adult patients who have received at least one prior therapy. The approval is based on the results of two studies in which overall response rate was the primary endpoint.
BGB-3111-206 (NCT03206970) was a phase 2, open-label, multicenter, single-arm trial of 86 patients with MCL who received at least one prior therapy. Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity. BGB-3111-AU-003 (NCT 02343120) was a phase 1/2, open-label, dose-escalation trial of B-cell malignancies, including 32 previously treated MCL patients treated with zanubrutinib at 160 mg twice daily or 320 mg once daily.
In the phase 2 trial, 18fluorodeoxyglucose (FDG)–PET scans were required and the ORR was 84% (95% confidence interval, 74%-91%), with a complete response rate of 59% (95% CI, 48%-70%) and a median response duration of 19.5 months (95% CI, 16.6% to not estimable). In the phase 1/2 dose-escalation trial, FDG-PET scans were not required and the ORR was 84% (95% CI, 67%-95%), with a complete response rate of 22% (95% CI, 9%-40%) and a median response duration of 18.5 months (95% CI, 12.6% to not estimable). In both trials, median follow-up on study was about 18 months.
The most common adverse reactions were cytopenias, upper respiratory tract infection, rash, bruising, diarrhea, and cough. The most common serious adverse reactions were pneumonia in 11% and hemorrhage in 5% of patients. Of 118 MCL patients, 8 stopped therapy because of an adverse event, most frequently pneumonia (3.4%).
How these results influence practice
Unfortunately, the therapy of recurrent MCL is noncurative, because of the rapid development of treatment resistance. There are multiple single-and multiagent chemotherapy regimens that may be tried, many incorporating immunotherapy options such as anti-CD20- or Bruton tyrosine kinase (BTK)–targeted agents. Given the limited efficacy of these agents, temporary nature of remissions, and paucity of data comparing these various treatment options, participation in clinical trials is encouraged whenever possible.
Outside of a clinical trial, zanubrutinib joins ibrutinib and acalabrutinib as approved single-agent BTK inhibitors for adult MCL patients in relapse. The impressive ORR and response duration reported for zanubrutinib are similar to the results achieved with the other agents, but the toxicity pattern may be slightly different.
As in the treatment of hormonally sensitive breast cancer, clinicians and patients benefit when they have multiple similar, equally efficacious oral agents with slightly different toxicity patterns so that quality of life can be improved and treatment duration maximized before treatment resistance develops and a more toxic and/or inconvenient therapy needs to be employed.
Whether zanubrutinib has benefits beyond those for MCL patients in relapse will depend on the results of confirmatory trials and patient-reported outcome data.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I Will Treat My Next Patient,” I highlight two recent drug approvals by the Food and Drug Administration – crizanlizumab for sickle cell patients with painful crises and zanubrutinib for mantle cell lymphoma (MCL) patients in relapse.
Crizanlizumab
P-selectin is an adhesion molecule expressed on activated vascular endothelial cells and platelets. It is a key molecule in the initiation of leukocyte rolling on vessel walls and promotes firm attachment and extravasation to underlying tissues during inflammation. Up-regulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interactions involved in the pathogenesis of sickle cell pain crises.
The SUSTAIN study was a multisite, placebo-controlled, randomized phase 2 trial of two different dosage levels of intravenous crizanlizumab (2.5 mg/kg or 5 mg/kg for 52 weeks), a humanized anti–P-selectin antibody, examining its effect on pain crises in patients with sickle cell disease. The primary endpoint was the annual rate of sickle cell pain crises, with a variety of clinically relevant secondary endpoints. The target population had 2-10 pain crises in the 12 months before enrollment. Patients on a stable dose of hydroxyurea for at least the most recent 3 months were allowed to enter, but if patients were not receiving hydroxyurea, it could not be initiated during the trial. Patients who were undergoing chronic red-cell transfusion therapy were excluded.
Among 198 enrolled patients, 35% did not complete the 52 weeks of treatment. Discontinuations were equally balanced among patients assigned to the high-dose, low-dose, and placebo cohorts. Adverse events associated with crizanlizumab included back pain, nausea, pyrexia, and arthralgia. Serious adverse events occurred in 55 patients, with 5 deaths, all of which were unrelated to treatment. Crizanlizumab did not augment hemolysis or bacterial infections.
In the efficacy analysis, patients receiving high-dose crizanlizumab had a median annual rate of 1.63 health care visits for sickle cell pain crises, compared with 2.98 visits for placebo patients (P = .01). In comparison with placebo, high-dose crizanlizumab also delayed the first pain crisis after starting treatment (4.1 months vs. 1.4 months), delayed the median time to a second pain crisis, and decreased the median number of pain crises annually.
More than twice as many high-dose crizanlizumab patients had no pain crisis episodes, compared with placebo patients. In general, differences were more striking in patients who were not taking hydroxyurea and who had non–hemoglobin SS disease. Differences in the primary endpoint between low-dose crizanlizumab and placebo were numerically, but not statistically, different.
How these results influence practice
It has been over 20 years since a new agent (hydroxyurea) was approved for sickle cell patients and, despite its use, sickle cell pain crises remain a frequent problem. Pain crises are associated with worse quality of life and increased risk of death. A promising advance is badly needed, especially in an era in which sensitivity to providers’ role in the opioid addiction crisis is highly scrutinized and may contribute to future undertreatment of pain episodes. This is especially true for patients from areas with high levels of opioid misuse.
The SUSTAIN trial was international, multi-institutional, placebo-controlled, and inclusive. These attributes enhance the likelihood that crizanlizumab will enhance patient care in routine practice. As an intravenous agent, monitoring adherence and toxicity are less challenging than with hydroxyurea. Despite these factors, however, there are some concerns. Crizanlizumab was not free of toxicity, quality of life via the Brief Pain Inventory used in the trial was not improved, and changes in the pain-severity and pain-interference domains were small. Treatment in SUSTAIN ensued for 52 weeks, so the emergence of late neutralizing antibodies and late toxicities with longer-term therapy will require careful postmarketing assessment.
These concerns notwithstanding, anyone who has cared for sickle cell patients would be excited about the potential benefits crizanlizumab could bring to patient care.
Zanubrutinib
The FDA has approved zanubrutinib for the treatment of MCL in adult patients who have received at least one prior therapy. The approval is based on the results of two studies in which overall response rate was the primary endpoint.
BGB-3111-206 (NCT03206970) was a phase 2, open-label, multicenter, single-arm trial of 86 patients with MCL who received at least one prior therapy. Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity. BGB-3111-AU-003 (NCT 02343120) was a phase 1/2, open-label, dose-escalation trial of B-cell malignancies, including 32 previously treated MCL patients treated with zanubrutinib at 160 mg twice daily or 320 mg once daily.
In the phase 2 trial, 18fluorodeoxyglucose (FDG)–PET scans were required and the ORR was 84% (95% confidence interval, 74%-91%), with a complete response rate of 59% (95% CI, 48%-70%) and a median response duration of 19.5 months (95% CI, 16.6% to not estimable). In the phase 1/2 dose-escalation trial, FDG-PET scans were not required and the ORR was 84% (95% CI, 67%-95%), with a complete response rate of 22% (95% CI, 9%-40%) and a median response duration of 18.5 months (95% CI, 12.6% to not estimable). In both trials, median follow-up on study was about 18 months.
The most common adverse reactions were cytopenias, upper respiratory tract infection, rash, bruising, diarrhea, and cough. The most common serious adverse reactions were pneumonia in 11% and hemorrhage in 5% of patients. Of 118 MCL patients, 8 stopped therapy because of an adverse event, most frequently pneumonia (3.4%).
How these results influence practice
Unfortunately, the therapy of recurrent MCL is noncurative, because of the rapid development of treatment resistance. There are multiple single-and multiagent chemotherapy regimens that may be tried, many incorporating immunotherapy options such as anti-CD20- or Bruton tyrosine kinase (BTK)–targeted agents. Given the limited efficacy of these agents, temporary nature of remissions, and paucity of data comparing these various treatment options, participation in clinical trials is encouraged whenever possible.
Outside of a clinical trial, zanubrutinib joins ibrutinib and acalabrutinib as approved single-agent BTK inhibitors for adult MCL patients in relapse. The impressive ORR and response duration reported for zanubrutinib are similar to the results achieved with the other agents, but the toxicity pattern may be slightly different.
As in the treatment of hormonally sensitive breast cancer, clinicians and patients benefit when they have multiple similar, equally efficacious oral agents with slightly different toxicity patterns so that quality of life can be improved and treatment duration maximized before treatment resistance develops and a more toxic and/or inconvenient therapy needs to be employed.
Whether zanubrutinib has benefits beyond those for MCL patients in relapse will depend on the results of confirmatory trials and patient-reported outcome data.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I Will Treat My Next Patient,” I highlight two recent drug approvals by the Food and Drug Administration – crizanlizumab for sickle cell patients with painful crises and zanubrutinib for mantle cell lymphoma (MCL) patients in relapse.
Crizanlizumab
P-selectin is an adhesion molecule expressed on activated vascular endothelial cells and platelets. It is a key molecule in the initiation of leukocyte rolling on vessel walls and promotes firm attachment and extravasation to underlying tissues during inflammation. Up-regulation of P-selectin on endothelial cells and platelets contributes to the cell-cell interactions involved in the pathogenesis of sickle cell pain crises.
The SUSTAIN study was a multisite, placebo-controlled, randomized phase 2 trial of two different dosage levels of intravenous crizanlizumab (2.5 mg/kg or 5 mg/kg for 52 weeks), a humanized anti–P-selectin antibody, examining its effect on pain crises in patients with sickle cell disease. The primary endpoint was the annual rate of sickle cell pain crises, with a variety of clinically relevant secondary endpoints. The target population had 2-10 pain crises in the 12 months before enrollment. Patients on a stable dose of hydroxyurea for at least the most recent 3 months were allowed to enter, but if patients were not receiving hydroxyurea, it could not be initiated during the trial. Patients who were undergoing chronic red-cell transfusion therapy were excluded.
Among 198 enrolled patients, 35% did not complete the 52 weeks of treatment. Discontinuations were equally balanced among patients assigned to the high-dose, low-dose, and placebo cohorts. Adverse events associated with crizanlizumab included back pain, nausea, pyrexia, and arthralgia. Serious adverse events occurred in 55 patients, with 5 deaths, all of which were unrelated to treatment. Crizanlizumab did not augment hemolysis or bacterial infections.
In the efficacy analysis, patients receiving high-dose crizanlizumab had a median annual rate of 1.63 health care visits for sickle cell pain crises, compared with 2.98 visits for placebo patients (P = .01). In comparison with placebo, high-dose crizanlizumab also delayed the first pain crisis after starting treatment (4.1 months vs. 1.4 months), delayed the median time to a second pain crisis, and decreased the median number of pain crises annually.
More than twice as many high-dose crizanlizumab patients had no pain crisis episodes, compared with placebo patients. In general, differences were more striking in patients who were not taking hydroxyurea and who had non–hemoglobin SS disease. Differences in the primary endpoint between low-dose crizanlizumab and placebo were numerically, but not statistically, different.
How these results influence practice
It has been over 20 years since a new agent (hydroxyurea) was approved for sickle cell patients and, despite its use, sickle cell pain crises remain a frequent problem. Pain crises are associated with worse quality of life and increased risk of death. A promising advance is badly needed, especially in an era in which sensitivity to providers’ role in the opioid addiction crisis is highly scrutinized and may contribute to future undertreatment of pain episodes. This is especially true for patients from areas with high levels of opioid misuse.
The SUSTAIN trial was international, multi-institutional, placebo-controlled, and inclusive. These attributes enhance the likelihood that crizanlizumab will enhance patient care in routine practice. As an intravenous agent, monitoring adherence and toxicity are less challenging than with hydroxyurea. Despite these factors, however, there are some concerns. Crizanlizumab was not free of toxicity, quality of life via the Brief Pain Inventory used in the trial was not improved, and changes in the pain-severity and pain-interference domains were small. Treatment in SUSTAIN ensued for 52 weeks, so the emergence of late neutralizing antibodies and late toxicities with longer-term therapy will require careful postmarketing assessment.
These concerns notwithstanding, anyone who has cared for sickle cell patients would be excited about the potential benefits crizanlizumab could bring to patient care.
Zanubrutinib
The FDA has approved zanubrutinib for the treatment of MCL in adult patients who have received at least one prior therapy. The approval is based on the results of two studies in which overall response rate was the primary endpoint.
BGB-3111-206 (NCT03206970) was a phase 2, open-label, multicenter, single-arm trial of 86 patients with MCL who received at least one prior therapy. Zanubrutinib was given orally at 160 mg twice daily until disease progression or unacceptable toxicity. BGB-3111-AU-003 (NCT 02343120) was a phase 1/2, open-label, dose-escalation trial of B-cell malignancies, including 32 previously treated MCL patients treated with zanubrutinib at 160 mg twice daily or 320 mg once daily.
In the phase 2 trial, 18fluorodeoxyglucose (FDG)–PET scans were required and the ORR was 84% (95% confidence interval, 74%-91%), with a complete response rate of 59% (95% CI, 48%-70%) and a median response duration of 19.5 months (95% CI, 16.6% to not estimable). In the phase 1/2 dose-escalation trial, FDG-PET scans were not required and the ORR was 84% (95% CI, 67%-95%), with a complete response rate of 22% (95% CI, 9%-40%) and a median response duration of 18.5 months (95% CI, 12.6% to not estimable). In both trials, median follow-up on study was about 18 months.
The most common adverse reactions were cytopenias, upper respiratory tract infection, rash, bruising, diarrhea, and cough. The most common serious adverse reactions were pneumonia in 11% and hemorrhage in 5% of patients. Of 118 MCL patients, 8 stopped therapy because of an adverse event, most frequently pneumonia (3.4%).
How these results influence practice
Unfortunately, the therapy of recurrent MCL is noncurative, because of the rapid development of treatment resistance. There are multiple single-and multiagent chemotherapy regimens that may be tried, many incorporating immunotherapy options such as anti-CD20- or Bruton tyrosine kinase (BTK)–targeted agents. Given the limited efficacy of these agents, temporary nature of remissions, and paucity of data comparing these various treatment options, participation in clinical trials is encouraged whenever possible.
Outside of a clinical trial, zanubrutinib joins ibrutinib and acalabrutinib as approved single-agent BTK inhibitors for adult MCL patients in relapse. The impressive ORR and response duration reported for zanubrutinib are similar to the results achieved with the other agents, but the toxicity pattern may be slightly different.
As in the treatment of hormonally sensitive breast cancer, clinicians and patients benefit when they have multiple similar, equally efficacious oral agents with slightly different toxicity patterns so that quality of life can be improved and treatment duration maximized before treatment resistance develops and a more toxic and/or inconvenient therapy needs to be employed.
Whether zanubrutinib has benefits beyond those for MCL patients in relapse will depend on the results of confirmatory trials and patient-reported outcome data.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.