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Antibody has ‘very promising activity’ in rel/ref CTCL
LA JOLLA, CA—An antibody targeting KIR3DL2 has “very promising activity” in relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to a speaker at the 10th Annual T-cell Lymphoma Forum.
The antibody, IPH4102, produced an overall response rate (ORR) of 44% in a phase 1 trial of CTCL patients, with an ORR of 50% in patients with Sézary syndrome (SS).
There were 2 serious adverse events (AEs) that were considered possibly related to IPH4102, and 1 of these was fatal.
Youn H. Kim, MD, of Stanford Cancer Institute in Palo Alto, California, presented these results at this year’s T-cell Lymphoma Forum. The research was sponsored by Innate Pharma, the company developing IPH4102.
“KIR3DL2 is a target that’s a member of the killer immunoglobulin-like receptor [KIR] family, and it’s also very specifically expressed in CTCL,” Dr Kim explained. “The antibody [IPH4102] is Fc-modified to enhance the antibody-dependent cell cytotoxicity and also works by antibody-dependent cell phagocytosis. It binds and, with the immunologic effect, kills the cancer cells.”
“[IPH4102] is specific for cancer cells because [KIR3DL2] is only minimally expressed in normal T cells as well as natural killer [NK] cells. About a third of NK cells that do express [KIR3DL2] don’t get affected [by IPH4102]. So it looks like the killer cells don’t kill each other, and they specifically target the neoplastic cells.”
Patients
Dr Kim and her colleagues have tested IPH4102 in 25 patients with relapsed/refractory CTCL—20 with SS, 4 with mycosis fungoides (MF), and 1 with CD4+ CTCL not otherwise specified. At baseline, patients had a median age of 71 (range, 42-90).
The patients had received a median of 4 prior systemic regimens (range, 2-10). Among the MF and SS patients, 1 patient had stage IB disease, 3 had stage IIB, and 20 had stage IVA disease.
Treatment
This study has a dose-escalation portion (accelerated 3+3 design) and an expansion portion. Dr Kim presented results for the 25 patients in the dose-escalation portion, which was completed in May 2017.
Patients received IPH4102 at 10 dose levels, ranging from 0.0001 mg/kg to 10 mg/kg. They received the drug once weekly for 4 doses, every 2 weeks for 10 doses, and every 4 weeks thereafter. They were treated until progression or unacceptable toxicity.
The expansion cohorts (which include SS and transformed MF patients) started enrolling in July 2017, with patients receiving IPH4102 at the recommended phase 2 dose—750 mg.
Safety
There were no dose-limiting toxicities with IPH4102. So the equivalent of 10 mg/kg—a 750 mg flat dose—was deemed the recommended phase 2 (and expansion) dose.
The incidence of AEs was 92% (n=23), and the incidence of treatment-related AEs was 52% (n=13).
Treatment-related AEs included lymphopenia (16%, n=4), asthenia (12%, n=3), nausea (8%, n=2), chills (8%, n=2), pyrexia (8%, n=2), arthralgia (8%, n=2), and muscle spasms (8%, n=2).
Eight patients had serious AEs, and 2 had serious AEs that were considered possibly related to treatment.
One patient had grade 2 atrial flutter diagnosed 1 hour after the first dose of IPH4102. The patient had a history of cardiac arrhythmia. She was hospitalized after the atrial flutter, received amiodarone, and the arrhythmia resolved. She went on to receive 15 more doses of IPH4102 without recurrence.
The other patient with a serious AE considered possibly related to treatment had hepatitis that occurred 6 weeks after the last dose of IPH4102. The patient had discontinued treatment due to progression after receiving IPH4102 for a year and achieving a partial response (PR).
This patient ultimately died of the hepatitis. Another fatal AE, considered unrelated to treatment, was Staphylococcus aureus sepsis.
“The safety looks very solid,” Dr Kim said, “[with] very low numbers of any significant severe adverse effects.”
Efficacy
The best global ORR was 44%, with 10 PRs and 1 complete response (CR). Twelve patients had stable disease, and 2 progressed.
In patients with SS, the best global ORR was 50%. One patient had a CR, 9 had PRs, and 8 had stable disease. The ORR was 60% in the skin and a 65% in the blood compartment for patients with SS.
Four responses were ongoing at last follow-up. The median follow-up was 15 months.
The median duration of response for the entire cohort was 8.2 months (range, 64 days to 519+ days). For SS patients, the median duration of response was 9.9 months (range, 64 days to 519+ days).
The median progression-free survival was 9.8 months overall (range, 28 days to 610+ days). For SS patients, the median progression-free survival was 10.8 months (range, 28 days to 610+ days).
“So with the efficacy and the safety profile, we are really hoping to get this drug to the phase 2 level and are excited to move forward,” Dr Kim concluded.
LA JOLLA, CA—An antibody targeting KIR3DL2 has “very promising activity” in relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to a speaker at the 10th Annual T-cell Lymphoma Forum.
The antibody, IPH4102, produced an overall response rate (ORR) of 44% in a phase 1 trial of CTCL patients, with an ORR of 50% in patients with Sézary syndrome (SS).
There were 2 serious adverse events (AEs) that were considered possibly related to IPH4102, and 1 of these was fatal.
Youn H. Kim, MD, of Stanford Cancer Institute in Palo Alto, California, presented these results at this year’s T-cell Lymphoma Forum. The research was sponsored by Innate Pharma, the company developing IPH4102.
“KIR3DL2 is a target that’s a member of the killer immunoglobulin-like receptor [KIR] family, and it’s also very specifically expressed in CTCL,” Dr Kim explained. “The antibody [IPH4102] is Fc-modified to enhance the antibody-dependent cell cytotoxicity and also works by antibody-dependent cell phagocytosis. It binds and, with the immunologic effect, kills the cancer cells.”
“[IPH4102] is specific for cancer cells because [KIR3DL2] is only minimally expressed in normal T cells as well as natural killer [NK] cells. About a third of NK cells that do express [KIR3DL2] don’t get affected [by IPH4102]. So it looks like the killer cells don’t kill each other, and they specifically target the neoplastic cells.”
Patients
Dr Kim and her colleagues have tested IPH4102 in 25 patients with relapsed/refractory CTCL—20 with SS, 4 with mycosis fungoides (MF), and 1 with CD4+ CTCL not otherwise specified. At baseline, patients had a median age of 71 (range, 42-90).
The patients had received a median of 4 prior systemic regimens (range, 2-10). Among the MF and SS patients, 1 patient had stage IB disease, 3 had stage IIB, and 20 had stage IVA disease.
Treatment
This study has a dose-escalation portion (accelerated 3+3 design) and an expansion portion. Dr Kim presented results for the 25 patients in the dose-escalation portion, which was completed in May 2017.
Patients received IPH4102 at 10 dose levels, ranging from 0.0001 mg/kg to 10 mg/kg. They received the drug once weekly for 4 doses, every 2 weeks for 10 doses, and every 4 weeks thereafter. They were treated until progression or unacceptable toxicity.
The expansion cohorts (which include SS and transformed MF patients) started enrolling in July 2017, with patients receiving IPH4102 at the recommended phase 2 dose—750 mg.
Safety
There were no dose-limiting toxicities with IPH4102. So the equivalent of 10 mg/kg—a 750 mg flat dose—was deemed the recommended phase 2 (and expansion) dose.
The incidence of AEs was 92% (n=23), and the incidence of treatment-related AEs was 52% (n=13).
Treatment-related AEs included lymphopenia (16%, n=4), asthenia (12%, n=3), nausea (8%, n=2), chills (8%, n=2), pyrexia (8%, n=2), arthralgia (8%, n=2), and muscle spasms (8%, n=2).
Eight patients had serious AEs, and 2 had serious AEs that were considered possibly related to treatment.
One patient had grade 2 atrial flutter diagnosed 1 hour after the first dose of IPH4102. The patient had a history of cardiac arrhythmia. She was hospitalized after the atrial flutter, received amiodarone, and the arrhythmia resolved. She went on to receive 15 more doses of IPH4102 without recurrence.
The other patient with a serious AE considered possibly related to treatment had hepatitis that occurred 6 weeks after the last dose of IPH4102. The patient had discontinued treatment due to progression after receiving IPH4102 for a year and achieving a partial response (PR).
This patient ultimately died of the hepatitis. Another fatal AE, considered unrelated to treatment, was Staphylococcus aureus sepsis.
“The safety looks very solid,” Dr Kim said, “[with] very low numbers of any significant severe adverse effects.”
Efficacy
The best global ORR was 44%, with 10 PRs and 1 complete response (CR). Twelve patients had stable disease, and 2 progressed.
In patients with SS, the best global ORR was 50%. One patient had a CR, 9 had PRs, and 8 had stable disease. The ORR was 60% in the skin and a 65% in the blood compartment for patients with SS.
Four responses were ongoing at last follow-up. The median follow-up was 15 months.
The median duration of response for the entire cohort was 8.2 months (range, 64 days to 519+ days). For SS patients, the median duration of response was 9.9 months (range, 64 days to 519+ days).
The median progression-free survival was 9.8 months overall (range, 28 days to 610+ days). For SS patients, the median progression-free survival was 10.8 months (range, 28 days to 610+ days).
“So with the efficacy and the safety profile, we are really hoping to get this drug to the phase 2 level and are excited to move forward,” Dr Kim concluded.
LA JOLLA, CA—An antibody targeting KIR3DL2 has “very promising activity” in relapsed/refractory cutaneous T-cell lymphoma (CTCL), according to a speaker at the 10th Annual T-cell Lymphoma Forum.
The antibody, IPH4102, produced an overall response rate (ORR) of 44% in a phase 1 trial of CTCL patients, with an ORR of 50% in patients with Sézary syndrome (SS).
There were 2 serious adverse events (AEs) that were considered possibly related to IPH4102, and 1 of these was fatal.
Youn H. Kim, MD, of Stanford Cancer Institute in Palo Alto, California, presented these results at this year’s T-cell Lymphoma Forum. The research was sponsored by Innate Pharma, the company developing IPH4102.
“KIR3DL2 is a target that’s a member of the killer immunoglobulin-like receptor [KIR] family, and it’s also very specifically expressed in CTCL,” Dr Kim explained. “The antibody [IPH4102] is Fc-modified to enhance the antibody-dependent cell cytotoxicity and also works by antibody-dependent cell phagocytosis. It binds and, with the immunologic effect, kills the cancer cells.”
“[IPH4102] is specific for cancer cells because [KIR3DL2] is only minimally expressed in normal T cells as well as natural killer [NK] cells. About a third of NK cells that do express [KIR3DL2] don’t get affected [by IPH4102]. So it looks like the killer cells don’t kill each other, and they specifically target the neoplastic cells.”
Patients
Dr Kim and her colleagues have tested IPH4102 in 25 patients with relapsed/refractory CTCL—20 with SS, 4 with mycosis fungoides (MF), and 1 with CD4+ CTCL not otherwise specified. At baseline, patients had a median age of 71 (range, 42-90).
The patients had received a median of 4 prior systemic regimens (range, 2-10). Among the MF and SS patients, 1 patient had stage IB disease, 3 had stage IIB, and 20 had stage IVA disease.
Treatment
This study has a dose-escalation portion (accelerated 3+3 design) and an expansion portion. Dr Kim presented results for the 25 patients in the dose-escalation portion, which was completed in May 2017.
Patients received IPH4102 at 10 dose levels, ranging from 0.0001 mg/kg to 10 mg/kg. They received the drug once weekly for 4 doses, every 2 weeks for 10 doses, and every 4 weeks thereafter. They were treated until progression or unacceptable toxicity.
The expansion cohorts (which include SS and transformed MF patients) started enrolling in July 2017, with patients receiving IPH4102 at the recommended phase 2 dose—750 mg.
Safety
There were no dose-limiting toxicities with IPH4102. So the equivalent of 10 mg/kg—a 750 mg flat dose—was deemed the recommended phase 2 (and expansion) dose.
The incidence of AEs was 92% (n=23), and the incidence of treatment-related AEs was 52% (n=13).
Treatment-related AEs included lymphopenia (16%, n=4), asthenia (12%, n=3), nausea (8%, n=2), chills (8%, n=2), pyrexia (8%, n=2), arthralgia (8%, n=2), and muscle spasms (8%, n=2).
Eight patients had serious AEs, and 2 had serious AEs that were considered possibly related to treatment.
One patient had grade 2 atrial flutter diagnosed 1 hour after the first dose of IPH4102. The patient had a history of cardiac arrhythmia. She was hospitalized after the atrial flutter, received amiodarone, and the arrhythmia resolved. She went on to receive 15 more doses of IPH4102 without recurrence.
The other patient with a serious AE considered possibly related to treatment had hepatitis that occurred 6 weeks after the last dose of IPH4102. The patient had discontinued treatment due to progression after receiving IPH4102 for a year and achieving a partial response (PR).
This patient ultimately died of the hepatitis. Another fatal AE, considered unrelated to treatment, was Staphylococcus aureus sepsis.
“The safety looks very solid,” Dr Kim said, “[with] very low numbers of any significant severe adverse effects.”
Efficacy
The best global ORR was 44%, with 10 PRs and 1 complete response (CR). Twelve patients had stable disease, and 2 progressed.
In patients with SS, the best global ORR was 50%. One patient had a CR, 9 had PRs, and 8 had stable disease. The ORR was 60% in the skin and a 65% in the blood compartment for patients with SS.
Four responses were ongoing at last follow-up. The median follow-up was 15 months.
The median duration of response for the entire cohort was 8.2 months (range, 64 days to 519+ days). For SS patients, the median duration of response was 9.9 months (range, 64 days to 519+ days).
The median progression-free survival was 9.8 months overall (range, 28 days to 610+ days). For SS patients, the median progression-free survival was 10.8 months (range, 28 days to 610+ days).
“So with the efficacy and the safety profile, we are really hoping to get this drug to the phase 2 level and are excited to move forward,” Dr Kim concluded.
ASCO, NCCN release guidelines on checkpoint inhibitors
Two cancer organizations have released guidelines for managing the side effects of immune checkpoint inhibitors.
The American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network® (NCCN) developed these guidelines because patients who receive immune checkpoint inhibitors experience unique side effects that can be severe, irreversible, and life-threatening.
Given that checkpoint inhibitors have entered the clinic fairly recently, clinicians may need guidance in recognizing and treating these side effects.
“With rapidly increasing use of immune checkpoint inhibitors, it is imperative that clinicians are knowledgeable about their unique toxicity profiles,” said ASCO Chief Executive Officer Clifford A. Hudis, MD.
“These new guidelines from ASCO and NCCN will help our community continue to provide the highest quality of care to all patients as they incorporate these agents into routine care.”
To the develop their guidelines, ASCO and NCCN convened multidisciplinary panels with representation from hematology, oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, emergency medicine, and nursing, as well as patient advocacy experts.
The clinical recommendations are based on a systematic review of the literature and an informal consensus process. The recommendations pertain only to checkpoint inhibitors currently approved in the US—pembrolizumab, nivolumab, atezolizumab, avelumab, ipilimumab, and durvalumab.
Key recommendations from the guidelines include:
- In general, checkpoint inhibitors can be continued with close monitoring if patients experience grade 1 toxicities, with the exception of some neurologic, cardiac, and hematologic toxicities.
- For grade 2 toxicities, checkpoint inhibitors should be held until symptoms and/or lab values revert to grade 1 levels or lower. Corticosteroids may be offered.
- For grade 3 toxicities, patients should receive high-dose corticosteroids for at least 6 weeks. Extreme caution is recommended when restarting immunotherapy after grade 3 toxicity, if it is restarted at all.
- In general, grade 4 toxicities necessitate stopping checkpoint inhibitor therapy permanently.
Consult the guidelines for specific recommendations.
ASCO’s guidelines, “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline,” have been published in the Journal of Clinical Oncology.
NCCN’s guidelines, “Management of Immunotherapy-Related Toxicities (Immune Checkpoint Inhibitor-Related Toxicities),” are available on the NCCN website.
Two cancer organizations have released guidelines for managing the side effects of immune checkpoint inhibitors.
The American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network® (NCCN) developed these guidelines because patients who receive immune checkpoint inhibitors experience unique side effects that can be severe, irreversible, and life-threatening.
Given that checkpoint inhibitors have entered the clinic fairly recently, clinicians may need guidance in recognizing and treating these side effects.
“With rapidly increasing use of immune checkpoint inhibitors, it is imperative that clinicians are knowledgeable about their unique toxicity profiles,” said ASCO Chief Executive Officer Clifford A. Hudis, MD.
“These new guidelines from ASCO and NCCN will help our community continue to provide the highest quality of care to all patients as they incorporate these agents into routine care.”
To the develop their guidelines, ASCO and NCCN convened multidisciplinary panels with representation from hematology, oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, emergency medicine, and nursing, as well as patient advocacy experts.
The clinical recommendations are based on a systematic review of the literature and an informal consensus process. The recommendations pertain only to checkpoint inhibitors currently approved in the US—pembrolizumab, nivolumab, atezolizumab, avelumab, ipilimumab, and durvalumab.
Key recommendations from the guidelines include:
- In general, checkpoint inhibitors can be continued with close monitoring if patients experience grade 1 toxicities, with the exception of some neurologic, cardiac, and hematologic toxicities.
- For grade 2 toxicities, checkpoint inhibitors should be held until symptoms and/or lab values revert to grade 1 levels or lower. Corticosteroids may be offered.
- For grade 3 toxicities, patients should receive high-dose corticosteroids for at least 6 weeks. Extreme caution is recommended when restarting immunotherapy after grade 3 toxicity, if it is restarted at all.
- In general, grade 4 toxicities necessitate stopping checkpoint inhibitor therapy permanently.
Consult the guidelines for specific recommendations.
ASCO’s guidelines, “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline,” have been published in the Journal of Clinical Oncology.
NCCN’s guidelines, “Management of Immunotherapy-Related Toxicities (Immune Checkpoint Inhibitor-Related Toxicities),” are available on the NCCN website.
Two cancer organizations have released guidelines for managing the side effects of immune checkpoint inhibitors.
The American Society of Clinical Oncology (ASCO) and National Comprehensive Cancer Network® (NCCN) developed these guidelines because patients who receive immune checkpoint inhibitors experience unique side effects that can be severe, irreversible, and life-threatening.
Given that checkpoint inhibitors have entered the clinic fairly recently, clinicians may need guidance in recognizing and treating these side effects.
“With rapidly increasing use of immune checkpoint inhibitors, it is imperative that clinicians are knowledgeable about their unique toxicity profiles,” said ASCO Chief Executive Officer Clifford A. Hudis, MD.
“These new guidelines from ASCO and NCCN will help our community continue to provide the highest quality of care to all patients as they incorporate these agents into routine care.”
To the develop their guidelines, ASCO and NCCN convened multidisciplinary panels with representation from hematology, oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, emergency medicine, and nursing, as well as patient advocacy experts.
The clinical recommendations are based on a systematic review of the literature and an informal consensus process. The recommendations pertain only to checkpoint inhibitors currently approved in the US—pembrolizumab, nivolumab, atezolizumab, avelumab, ipilimumab, and durvalumab.
Key recommendations from the guidelines include:
- In general, checkpoint inhibitors can be continued with close monitoring if patients experience grade 1 toxicities, with the exception of some neurologic, cardiac, and hematologic toxicities.
- For grade 2 toxicities, checkpoint inhibitors should be held until symptoms and/or lab values revert to grade 1 levels or lower. Corticosteroids may be offered.
- For grade 3 toxicities, patients should receive high-dose corticosteroids for at least 6 weeks. Extreme caution is recommended when restarting immunotherapy after grade 3 toxicity, if it is restarted at all.
- In general, grade 4 toxicities necessitate stopping checkpoint inhibitor therapy permanently.
Consult the guidelines for specific recommendations.
ASCO’s guidelines, “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline,” have been published in the Journal of Clinical Oncology.
NCCN’s guidelines, “Management of Immunotherapy-Related Toxicities (Immune Checkpoint Inhibitor-Related Toxicities),” are available on the NCCN website.
A view from the bridge to transplant for PTCL
LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.
“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”
“They’d finish ICE, get a 3- or 4-week break, get a transplant, leave the hospital 3 or 4 weeks later, and then usually by their first repeat scan, at least on average, those patients had already progressed, so we sort of cooled to the idea of auto transplant and started preferentially looking at allo if we were going to treat with curative intent in the relapsed setting,” he said.
In contrast to autologous SCT, the Memorial Sloan Kettering experience with allogeneic SCT for 65 patients with relapsed PTCL showed a 2-year overall survival rate of 59%, 2-year PFS rate of 48%, and a median PFS of 20.3 months. However, the rate of 1-year transplant-related mortality was still relatively high, at 17%, Dr. Horwitz acknowledged (ASH 2015. Abstract 4392).
An updated retrospective analysis of the center’s experience treating mature T-cell lymphoma patients with allogeneic SCT, also presented at the 2018 T-cell Lymphoma Forum, showed that disease status at transplant was one of the most important predictors of outcome. Median posttransplant PFS for patients in complete remission (CR) at the time of transplant was 61.3 months, compared with 11.4 months for patients in partial remission, 14 months for patients with stable disease, and 6.4 months for patients with disease progression (TCLF 2018. Abstract TM18_9).
“I think we can probably infer from [this] that CR not only gives you a better outcome with allo, but probably increases your chance that you get to an allo,” he said.
In the randomized phase 3 Lumiere study comparing the Aurora A kinase inhibitor alisertib with investigators’ choice of therapy in relapsed/refractory PTCL, alisertib was associated with a CR rate of 19%, whereas pralatrexate, gemcitabine, and romidepsin were associated with CR rates of 29%, 23%, and 33%, respectively, putting them on par with combination chemotherapy.
“I think many of us prefer some of the newer single agents because we’re really going for a durable maintenance of disease control rather than short-term bridge to transplant, but these drugs can provide adequate responses to transition over,” he said.
Better approaches by subtype?
The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.
In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).
A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.
For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
Timing may also matter
Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.
The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.
Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.
“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”
“They’d finish ICE, get a 3- or 4-week break, get a transplant, leave the hospital 3 or 4 weeks later, and then usually by their first repeat scan, at least on average, those patients had already progressed, so we sort of cooled to the idea of auto transplant and started preferentially looking at allo if we were going to treat with curative intent in the relapsed setting,” he said.
In contrast to autologous SCT, the Memorial Sloan Kettering experience with allogeneic SCT for 65 patients with relapsed PTCL showed a 2-year overall survival rate of 59%, 2-year PFS rate of 48%, and a median PFS of 20.3 months. However, the rate of 1-year transplant-related mortality was still relatively high, at 17%, Dr. Horwitz acknowledged (ASH 2015. Abstract 4392).
An updated retrospective analysis of the center’s experience treating mature T-cell lymphoma patients with allogeneic SCT, also presented at the 2018 T-cell Lymphoma Forum, showed that disease status at transplant was one of the most important predictors of outcome. Median posttransplant PFS for patients in complete remission (CR) at the time of transplant was 61.3 months, compared with 11.4 months for patients in partial remission, 14 months for patients with stable disease, and 6.4 months for patients with disease progression (TCLF 2018. Abstract TM18_9).
“I think we can probably infer from [this] that CR not only gives you a better outcome with allo, but probably increases your chance that you get to an allo,” he said.
In the randomized phase 3 Lumiere study comparing the Aurora A kinase inhibitor alisertib with investigators’ choice of therapy in relapsed/refractory PTCL, alisertib was associated with a CR rate of 19%, whereas pralatrexate, gemcitabine, and romidepsin were associated with CR rates of 29%, 23%, and 33%, respectively, putting them on par with combination chemotherapy.
“I think many of us prefer some of the newer single agents because we’re really going for a durable maintenance of disease control rather than short-term bridge to transplant, but these drugs can provide adequate responses to transition over,” he said.
Better approaches by subtype?
The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.
In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).
A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.
For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
Timing may also matter
Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.
The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.
Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – For patients with relapsed peripheral T-cell lymphoma, allogeneic stem cell transplants offer the best chance for achieving remission or even a cure, making the choice of therapies as bridges to transplant essential for getting there.
“The goal is to get to transplant with a curative intent. In our hands, that’s mostly allo[geneic] and mostly in the relapsed setting,” Steven M. Horwitz, MD, from the lymphoma service at Memorial Sloan Kettering Cancer Center, New York, said at the annual T-cell Lymphoma Forum. “The best bridge to transplant is the one that gets you across safely.”
“They’d finish ICE, get a 3- or 4-week break, get a transplant, leave the hospital 3 or 4 weeks later, and then usually by their first repeat scan, at least on average, those patients had already progressed, so we sort of cooled to the idea of auto transplant and started preferentially looking at allo if we were going to treat with curative intent in the relapsed setting,” he said.
In contrast to autologous SCT, the Memorial Sloan Kettering experience with allogeneic SCT for 65 patients with relapsed PTCL showed a 2-year overall survival rate of 59%, 2-year PFS rate of 48%, and a median PFS of 20.3 months. However, the rate of 1-year transplant-related mortality was still relatively high, at 17%, Dr. Horwitz acknowledged (ASH 2015. Abstract 4392).
An updated retrospective analysis of the center’s experience treating mature T-cell lymphoma patients with allogeneic SCT, also presented at the 2018 T-cell Lymphoma Forum, showed that disease status at transplant was one of the most important predictors of outcome. Median posttransplant PFS for patients in complete remission (CR) at the time of transplant was 61.3 months, compared with 11.4 months for patients in partial remission, 14 months for patients with stable disease, and 6.4 months for patients with disease progression (TCLF 2018. Abstract TM18_9).
“I think we can probably infer from [this] that CR not only gives you a better outcome with allo, but probably increases your chance that you get to an allo,” he said.
In the randomized phase 3 Lumiere study comparing the Aurora A kinase inhibitor alisertib with investigators’ choice of therapy in relapsed/refractory PTCL, alisertib was associated with a CR rate of 19%, whereas pralatrexate, gemcitabine, and romidepsin were associated with CR rates of 29%, 23%, and 33%, respectively, putting them on par with combination chemotherapy.
“I think many of us prefer some of the newer single agents because we’re really going for a durable maintenance of disease control rather than short-term bridge to transplant, but these drugs can provide adequate responses to transition over,” he said.
Better approaches by subtype?
The subtype of PTCL also appears to matter. Three approved agents for relapsed/refractory PTCL – belinostat (Beleodaq), romidepsin (Istodax), and pralatrexate (Folotyn) – are associated with CR rates of 11%, 15%, and 11%, respectively. But one PTCL subtype, anaplastic large cell lymphoma, appears particularly sensitive to treatment with brentuximab vedotin (Adcetris), with CR rates of 59%, Dr. Horwitz noted.
In a 2014 study, investigators reported that of the nine patients with anaplastic large cell lymphoma positive for anaplastic lymphoma kinase and treated with the anaplastic lymphoma kinase inhibitor crizotinib (Xalkori), all had a CR, with response durations stretching pasting 40 months in one patient, and past 30 months in two others (J Natl Cancer Inst. 2014 Feb;106[2]:djt378).
A different subtype, natural killer/T-cell lymphoma, was shown to be responsive to immunotherapy with pembrolizumab (Keytruda) in seven patients, with CRs in five and partial remissions in two. Responses to pembrolizumab in this PTCL subtype may be adequately long for getting patients to transplant, Dr. Horwitz said.
For some patients with angioimmunoblastic T-cell lymphoma, therapy with epigenetic modifying agents, such as decitabine or a combination of romidepsin and lenalidomide (Revlimid), with or without carfilzomib (Kyprolis), may also be effective bridges to transplant, based on the best available evidence.
Timing may also matter
Dr. Horwitz cautioned that for patients with cutaneous T-cell lymphoma, the investigational agent mogamulizumab, which was shown in the MAVORIC (Study of KW-0761 versus Vorinostat in Relapsed/Refractory CTCL) trial to offer significantly better PFS compared with vorinostat (Zolinza), also appears to increase the chance that patients will develop high-risk, potentially fatal graft vs. host disease posttransplant.
The risk appears to be slightly lower among patients who received the last dose of mogamulizumab more than 50 days before undergoing SCT, he noted.
Although there is no strong evidence to support it, Dr. Horwitz noted that the timing of most other therapies may also be important to the success of SCT. “I think we have seen that when patients have a big [long] break before transplant, the relapse rate is high, and I have a personal preference for using regimens that you can continue up close to transplant, because I think we lose [fewer] patients getting ready for that,” he said.
Dr. Horwitz had previously disclosed financial relationships with Celgene, Forty Seven, Huya Bioscience International, Infinity, Kyowa Hakko Kirin, Millennium, Seattle Genetics, and Takeda. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM TCLF 2018
Drug appears safe and active in PTCL, CTCL
LA JOLLA, CA—The dual PI3K δ/γ inhibitor tenalisib has demonstrated activity in a phase 1 trial of patients with relapsed/refractory T-cell lymphomas.
Tenalisib produced “encouraging” response rates of 44% in patients with cutaneous T-cell lymphoma (CTCL) and 50% in patients with peripheral T-cell lymphoma (PTCL), according to study investigator Bradley M. Haverkos, MD, of the University of Colorado School of Medicine in Aurora.
Dr Haverkos also said tenalisib had an acceptable safety profile.
The most common treatment-related adverse event (AE) in both patient groups was transaminitis.
Dr Haverkos and his colleagues presented these results in a pair of posters and an oral presentation at the 10th Annual T-cell Lymphoma Forum.
The trial was sponsored by Rhizen Pharmaceuticals, the company developing tenalisib (formerly RP6530).
The researchers have enrolled 55 patients in this trial—28 with CTCL and 27 with PTCL.
The study has a standard 3+3 design, starting with a 200 mg daily fasting dose of tenalisib and escalating to an 800 mg daily fasting dose, followed by an 800 mg daily fed cohort.
There were 3 dose-limiting toxicities in the 800 mg fed cohort—transaminitis, rash, and neutropenia. Therefore, the 800 mg fasting dose was considered the maximum-tolerated dose.
Patients in the PTCL and CTCL expansion cohorts received the maximum-tolerated dose.
Patients were scheduled to receive 8 cycles (28 days each) of tenalisib, but treatment could be extended to 24 months.
The data cutoff was January 10, 2018.
Efficacy in PTCL
Most PTCL patients (n=24) had PTCL not otherwise specified (NOS), 2 had angioimmunoblastic T-cell lymphoma (AITL), and 1 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL).
The patients’ median age at baseline was 63 (range, 40-89), and 63% are male. Sixty-three percent of patients had relapsed disease at baseline, 37% were refractory, and 93% had stage 3 or 4 disease. Patients had received a median of 3 prior therapies (range, 1-7).
The median duration of treatment with tenalisib was 1.9 months.
Fourteen patients were evaluable for efficacy. Eleven patients had progressed prior to the first protocol-defined assessment, and 2 patients had not reached their first efficacy assessment at the data cutoff.
Seven of the 14 evaluable patients responded (50%). Three patients (21%) had a complete response (CR), 4 (29%) had a partial response (PR), 3 (21%) had stable disease, and 4 (29%) progressed.
“There were several patients with lengthy responses,” Dr Haverkos noted. “One patient had an ongoing response at 16 months, another at 11 months, and a number of patients had ongoing responses at 7 months.”
All 3 patients with a CR had PTCL NOS and received the 800 mg fasting dose of tenalisib.
Two patients with a PR had PTCL NOS, 1 had AITL, and 1 had SPTCL. The SPTCL patient received the 200 mg dose.
The AITL patient and 1 of the PTCL NOS patients received the 800 mg fasting dose. The other PTCL NOS patient received the 400 mg dose.
Efficacy in CTCL
Most CTCL patients (n=23) had mycosis fungoides, but 5 had Sézary syndrome. The patients’ median age at baseline was 68 (range, 39-84), and 57% are female.
Forty-three percent of patients had relapsed disease at baseline, 57% were refractory, and 46% had stage 3 or 4 disease. Patients had received a median of 6 prior therapies (range, 2-15).
The median duration of treatment with tenalisib was 3.4 months.
Eighteen patients were evaluable for efficacy. Eight patients had progressed prior to the first protocol-defined assessment, and 2 patients had not yet reached their first efficacy assessment.
Eight of the 18 evaluable patients responded (44%), all with PRs. Seven patients (39%) had stable disease, and 3 (17%) progressed.
Four patients were still in response beyond 8 months of follow-up, and 1 patient was still in PR beyond 11 months.
Five patients with a PR had received the 800 mg fasting dose of tenalisib. Two received the 800 mg fed dose, and 1 patient received the drug at 400 mg.
Overall safety
Treatment-related AEs included transaminitis (25%, 14/55), diarrhea (11%, n=6), fatigue (6%, n=11), headache (9%, n=5), rash (9%, n=5), nausea (5%, n=3), vomiting (5%, n=3), pyrexia (5%, n=3), and dizziness (5%, n=3). Dizziness was only observed in CTCL patients.
Treatment-related grade 3 or higher AEs included transaminitis (20%, n=11), rash (5%, n=3), neutropenia (2%, n=1), hypophosphatemia (2%, n=1), international normalized ratio increase (2%, n=1), sepsis (2%, n=1), pyrexia (2%, n=1), and diplopia secondary to neuropathy (2%, n=1).
Seventy-six percent (n=42) of patients discontinued treatment. Sixty-eight percent (n=29) stopped due to progression, 5% (n=2) stopped at investigators’ discretion, 9% (n=4) withdrew consent, 12% (n=5) had a treatment-related AE, and 5% (n=2) had an unrelated AE.
Seventeen PTCL patients stopped treatment due to progression, as did 12 CTCL patients. One patient in each group stopped treatment at investigators’ discretion, and all 4 patients who withdrew consent had CTCL.
Four CTCL patients stopped treatment due to a related AE—transaminitis, sepsis, diarrhea, and diplopia secondary to neuropathy. One PTCL patient stopped treatment due to a related AE, which was transaminitis.
“Tenalisib at the 800 mg fasting dose has demonstrated acceptable safety and tolerability,” Dr Haverkos concluded. “We’ve observed encouraging response rates thus far, which support further evaluation of tenalisib in these patients.” 
LA JOLLA, CA—The dual PI3K δ/γ inhibitor tenalisib has demonstrated activity in a phase 1 trial of patients with relapsed/refractory T-cell lymphomas.
Tenalisib produced “encouraging” response rates of 44% in patients with cutaneous T-cell lymphoma (CTCL) and 50% in patients with peripheral T-cell lymphoma (PTCL), according to study investigator Bradley M. Haverkos, MD, of the University of Colorado School of Medicine in Aurora.
Dr Haverkos also said tenalisib had an acceptable safety profile.
The most common treatment-related adverse event (AE) in both patient groups was transaminitis.
Dr Haverkos and his colleagues presented these results in a pair of posters and an oral presentation at the 10th Annual T-cell Lymphoma Forum.
The trial was sponsored by Rhizen Pharmaceuticals, the company developing tenalisib (formerly RP6530).
The researchers have enrolled 55 patients in this trial—28 with CTCL and 27 with PTCL.
The study has a standard 3+3 design, starting with a 200 mg daily fasting dose of tenalisib and escalating to an 800 mg daily fasting dose, followed by an 800 mg daily fed cohort.
There were 3 dose-limiting toxicities in the 800 mg fed cohort—transaminitis, rash, and neutropenia. Therefore, the 800 mg fasting dose was considered the maximum-tolerated dose.
Patients in the PTCL and CTCL expansion cohorts received the maximum-tolerated dose.
Patients were scheduled to receive 8 cycles (28 days each) of tenalisib, but treatment could be extended to 24 months.
The data cutoff was January 10, 2018.
Efficacy in PTCL
Most PTCL patients (n=24) had PTCL not otherwise specified (NOS), 2 had angioimmunoblastic T-cell lymphoma (AITL), and 1 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL).
The patients’ median age at baseline was 63 (range, 40-89), and 63% are male. Sixty-three percent of patients had relapsed disease at baseline, 37% were refractory, and 93% had stage 3 or 4 disease. Patients had received a median of 3 prior therapies (range, 1-7).
The median duration of treatment with tenalisib was 1.9 months.
Fourteen patients were evaluable for efficacy. Eleven patients had progressed prior to the first protocol-defined assessment, and 2 patients had not reached their first efficacy assessment at the data cutoff.
Seven of the 14 evaluable patients responded (50%). Three patients (21%) had a complete response (CR), 4 (29%) had a partial response (PR), 3 (21%) had stable disease, and 4 (29%) progressed.
“There were several patients with lengthy responses,” Dr Haverkos noted. “One patient had an ongoing response at 16 months, another at 11 months, and a number of patients had ongoing responses at 7 months.”
All 3 patients with a CR had PTCL NOS and received the 800 mg fasting dose of tenalisib.
Two patients with a PR had PTCL NOS, 1 had AITL, and 1 had SPTCL. The SPTCL patient received the 200 mg dose.
The AITL patient and 1 of the PTCL NOS patients received the 800 mg fasting dose. The other PTCL NOS patient received the 400 mg dose.
Efficacy in CTCL
Most CTCL patients (n=23) had mycosis fungoides, but 5 had Sézary syndrome. The patients’ median age at baseline was 68 (range, 39-84), and 57% are female.
Forty-three percent of patients had relapsed disease at baseline, 57% were refractory, and 46% had stage 3 or 4 disease. Patients had received a median of 6 prior therapies (range, 2-15).
The median duration of treatment with tenalisib was 3.4 months.
Eighteen patients were evaluable for efficacy. Eight patients had progressed prior to the first protocol-defined assessment, and 2 patients had not yet reached their first efficacy assessment.
Eight of the 18 evaluable patients responded (44%), all with PRs. Seven patients (39%) had stable disease, and 3 (17%) progressed.
Four patients were still in response beyond 8 months of follow-up, and 1 patient was still in PR beyond 11 months.
Five patients with a PR had received the 800 mg fasting dose of tenalisib. Two received the 800 mg fed dose, and 1 patient received the drug at 400 mg.
Overall safety
Treatment-related AEs included transaminitis (25%, 14/55), diarrhea (11%, n=6), fatigue (6%, n=11), headache (9%, n=5), rash (9%, n=5), nausea (5%, n=3), vomiting (5%, n=3), pyrexia (5%, n=3), and dizziness (5%, n=3). Dizziness was only observed in CTCL patients.
Treatment-related grade 3 or higher AEs included transaminitis (20%, n=11), rash (5%, n=3), neutropenia (2%, n=1), hypophosphatemia (2%, n=1), international normalized ratio increase (2%, n=1), sepsis (2%, n=1), pyrexia (2%, n=1), and diplopia secondary to neuropathy (2%, n=1).
Seventy-six percent (n=42) of patients discontinued treatment. Sixty-eight percent (n=29) stopped due to progression, 5% (n=2) stopped at investigators’ discretion, 9% (n=4) withdrew consent, 12% (n=5) had a treatment-related AE, and 5% (n=2) had an unrelated AE.
Seventeen PTCL patients stopped treatment due to progression, as did 12 CTCL patients. One patient in each group stopped treatment at investigators’ discretion, and all 4 patients who withdrew consent had CTCL.
Four CTCL patients stopped treatment due to a related AE—transaminitis, sepsis, diarrhea, and diplopia secondary to neuropathy. One PTCL patient stopped treatment due to a related AE, which was transaminitis.
“Tenalisib at the 800 mg fasting dose has demonstrated acceptable safety and tolerability,” Dr Haverkos concluded. “We’ve observed encouraging response rates thus far, which support further evaluation of tenalisib in these patients.”
LA JOLLA, CA—The dual PI3K δ/γ inhibitor tenalisib has demonstrated activity in a phase 1 trial of patients with relapsed/refractory T-cell lymphomas.
Tenalisib produced “encouraging” response rates of 44% in patients with cutaneous T-cell lymphoma (CTCL) and 50% in patients with peripheral T-cell lymphoma (PTCL), according to study investigator Bradley M. Haverkos, MD, of the University of Colorado School of Medicine in Aurora.
Dr Haverkos also said tenalisib had an acceptable safety profile.
The most common treatment-related adverse event (AE) in both patient groups was transaminitis.
Dr Haverkos and his colleagues presented these results in a pair of posters and an oral presentation at the 10th Annual T-cell Lymphoma Forum.
The trial was sponsored by Rhizen Pharmaceuticals, the company developing tenalisib (formerly RP6530).
The researchers have enrolled 55 patients in this trial—28 with CTCL and 27 with PTCL.
The study has a standard 3+3 design, starting with a 200 mg daily fasting dose of tenalisib and escalating to an 800 mg daily fasting dose, followed by an 800 mg daily fed cohort.
There were 3 dose-limiting toxicities in the 800 mg fed cohort—transaminitis, rash, and neutropenia. Therefore, the 800 mg fasting dose was considered the maximum-tolerated dose.
Patients in the PTCL and CTCL expansion cohorts received the maximum-tolerated dose.
Patients were scheduled to receive 8 cycles (28 days each) of tenalisib, but treatment could be extended to 24 months.
The data cutoff was January 10, 2018.
Efficacy in PTCL
Most PTCL patients (n=24) had PTCL not otherwise specified (NOS), 2 had angioimmunoblastic T-cell lymphoma (AITL), and 1 had subcutaneous panniculitis-like T-cell lymphoma (SPTCL).
The patients’ median age at baseline was 63 (range, 40-89), and 63% are male. Sixty-three percent of patients had relapsed disease at baseline, 37% were refractory, and 93% had stage 3 or 4 disease. Patients had received a median of 3 prior therapies (range, 1-7).
The median duration of treatment with tenalisib was 1.9 months.
Fourteen patients were evaluable for efficacy. Eleven patients had progressed prior to the first protocol-defined assessment, and 2 patients had not reached their first efficacy assessment at the data cutoff.
Seven of the 14 evaluable patients responded (50%). Three patients (21%) had a complete response (CR), 4 (29%) had a partial response (PR), 3 (21%) had stable disease, and 4 (29%) progressed.
“There were several patients with lengthy responses,” Dr Haverkos noted. “One patient had an ongoing response at 16 months, another at 11 months, and a number of patients had ongoing responses at 7 months.”
All 3 patients with a CR had PTCL NOS and received the 800 mg fasting dose of tenalisib.
Two patients with a PR had PTCL NOS, 1 had AITL, and 1 had SPTCL. The SPTCL patient received the 200 mg dose.
The AITL patient and 1 of the PTCL NOS patients received the 800 mg fasting dose. The other PTCL NOS patient received the 400 mg dose.
Efficacy in CTCL
Most CTCL patients (n=23) had mycosis fungoides, but 5 had Sézary syndrome. The patients’ median age at baseline was 68 (range, 39-84), and 57% are female.
Forty-three percent of patients had relapsed disease at baseline, 57% were refractory, and 46% had stage 3 or 4 disease. Patients had received a median of 6 prior therapies (range, 2-15).
The median duration of treatment with tenalisib was 3.4 months.
Eighteen patients were evaluable for efficacy. Eight patients had progressed prior to the first protocol-defined assessment, and 2 patients had not yet reached their first efficacy assessment.
Eight of the 18 evaluable patients responded (44%), all with PRs. Seven patients (39%) had stable disease, and 3 (17%) progressed.
Four patients were still in response beyond 8 months of follow-up, and 1 patient was still in PR beyond 11 months.
Five patients with a PR had received the 800 mg fasting dose of tenalisib. Two received the 800 mg fed dose, and 1 patient received the drug at 400 mg.
Overall safety
Treatment-related AEs included transaminitis (25%, 14/55), diarrhea (11%, n=6), fatigue (6%, n=11), headache (9%, n=5), rash (9%, n=5), nausea (5%, n=3), vomiting (5%, n=3), pyrexia (5%, n=3), and dizziness (5%, n=3). Dizziness was only observed in CTCL patients.
Treatment-related grade 3 or higher AEs included transaminitis (20%, n=11), rash (5%, n=3), neutropenia (2%, n=1), hypophosphatemia (2%, n=1), international normalized ratio increase (2%, n=1), sepsis (2%, n=1), pyrexia (2%, n=1), and diplopia secondary to neuropathy (2%, n=1).
Seventy-six percent (n=42) of patients discontinued treatment. Sixty-eight percent (n=29) stopped due to progression, 5% (n=2) stopped at investigators’ discretion, 9% (n=4) withdrew consent, 12% (n=5) had a treatment-related AE, and 5% (n=2) had an unrelated AE.
Seventeen PTCL patients stopped treatment due to progression, as did 12 CTCL patients. One patient in each group stopped treatment at investigators’ discretion, and all 4 patients who withdrew consent had CTCL.
Four CTCL patients stopped treatment due to a related AE—transaminitis, sepsis, diarrhea, and diplopia secondary to neuropathy. One PTCL patient stopped treatment due to a related AE, which was transaminitis.
“Tenalisib at the 800 mg fasting dose has demonstrated acceptable safety and tolerability,” Dr Haverkos concluded. “We’ve observed encouraging response rates thus far, which support further evaluation of tenalisib in these patients.”
FIRST trial analysis shows more benefit for lenalidomide
Lenalidomide with low-dose dexamethasone showed a significant overall survival benefit, compared with melphalan with prednisone and thalidomide, for patients with transplant-ineligible newly diagnosed multiple myeloma, according to the final analysis of the phase 3 FIRST trial.
The prespecified final analysis evaluated overall survival (OS) at a follow-up of 60 months or longer, according to the study, which was published in Blood. The FIRST study included 1,623 patients randomized to receive lenalidomide with low-dose dexamethasone continuously until disease progression (Rd continuous), lenalidomide plus low-dose dexamethasone for 18 cycles instead of continuously (Rd18), or melphalan plus prednisone and thalidomide (MPT). Patients with high-risk cytogenetics were distributed evenly across the three treatment arms.
The Rd continuous cohort also experienced significantly longer PFS, compared with the MPT arm (HR, 0.69, 95% CI, 0.59-0.79, P less than .00001).
“Taken together, these findings suggest that Rd affords a clinical advantage in subsequent lines of therapy and highlight the importance of using Rd continuous and not MPT as first-line treatment of transplant-ineligible patients with [newly-diagnosed multiple myeloma],” the researchers wrote.
The OS benefit was similar for patients who received Rd continuous (59.1 months) and Rd18 (62.3 months). The researchers suggested that the similar survival could be due to a combination of factors, including the impact of subsequent lines of treatment and the older age of the patient population.
However, the benefit for Rd18 was not seen in the PFS analysis. Patients in the Rd18 group had a median PFS similar to that of patients in the MPT group (21 months vs. 21.9 months), both of which were shorter than the Rd continuous group (26 months).
The 4-year PFS more than doubled among patients in the Rd continuous arm (32.6%), compared with patients in both the Rd18 group (14.3%) and the MPT group (13.6%).
Patients in the Rd continuous group also experienced a decreased risk for progression or death, compared with patients in the Rd18 group (HR, 0.70, 95% CI, 0.60-0.81).
The researchers noted that no new safety concerns were observed in the final analysis. Second primary malignancies, including hematologic and solid tumors, were found in 36% of patients in the Rd continuous group, 38% of patients in the Rd18 group, and 46% of patients in the MPT group.
Celgene Corporation sponsored the study. Dr. Facon and his coauthors reported financial ties to various pharmaceutical companies, including Celgene.
SOURCE: Facon T et al. Blood. 2018 Jan 18;131(3):301-10.
Lenalidomide with low-dose dexamethasone showed a significant overall survival benefit, compared with melphalan with prednisone and thalidomide, for patients with transplant-ineligible newly diagnosed multiple myeloma, according to the final analysis of the phase 3 FIRST trial.
The prespecified final analysis evaluated overall survival (OS) at a follow-up of 60 months or longer, according to the study, which was published in Blood. The FIRST study included 1,623 patients randomized to receive lenalidomide with low-dose dexamethasone continuously until disease progression (Rd continuous), lenalidomide plus low-dose dexamethasone for 18 cycles instead of continuously (Rd18), or melphalan plus prednisone and thalidomide (MPT). Patients with high-risk cytogenetics were distributed evenly across the three treatment arms.
The Rd continuous cohort also experienced significantly longer PFS, compared with the MPT arm (HR, 0.69, 95% CI, 0.59-0.79, P less than .00001).
“Taken together, these findings suggest that Rd affords a clinical advantage in subsequent lines of therapy and highlight the importance of using Rd continuous and not MPT as first-line treatment of transplant-ineligible patients with [newly-diagnosed multiple myeloma],” the researchers wrote.
The OS benefit was similar for patients who received Rd continuous (59.1 months) and Rd18 (62.3 months). The researchers suggested that the similar survival could be due to a combination of factors, including the impact of subsequent lines of treatment and the older age of the patient population.
However, the benefit for Rd18 was not seen in the PFS analysis. Patients in the Rd18 group had a median PFS similar to that of patients in the MPT group (21 months vs. 21.9 months), both of which were shorter than the Rd continuous group (26 months).
The 4-year PFS more than doubled among patients in the Rd continuous arm (32.6%), compared with patients in both the Rd18 group (14.3%) and the MPT group (13.6%).
Patients in the Rd continuous group also experienced a decreased risk for progression or death, compared with patients in the Rd18 group (HR, 0.70, 95% CI, 0.60-0.81).
The researchers noted that no new safety concerns were observed in the final analysis. Second primary malignancies, including hematologic and solid tumors, were found in 36% of patients in the Rd continuous group, 38% of patients in the Rd18 group, and 46% of patients in the MPT group.
Celgene Corporation sponsored the study. Dr. Facon and his coauthors reported financial ties to various pharmaceutical companies, including Celgene.
SOURCE: Facon T et al. Blood. 2018 Jan 18;131(3):301-10.
Lenalidomide with low-dose dexamethasone showed a significant overall survival benefit, compared with melphalan with prednisone and thalidomide, for patients with transplant-ineligible newly diagnosed multiple myeloma, according to the final analysis of the phase 3 FIRST trial.
The prespecified final analysis evaluated overall survival (OS) at a follow-up of 60 months or longer, according to the study, which was published in Blood. The FIRST study included 1,623 patients randomized to receive lenalidomide with low-dose dexamethasone continuously until disease progression (Rd continuous), lenalidomide plus low-dose dexamethasone for 18 cycles instead of continuously (Rd18), or melphalan plus prednisone and thalidomide (MPT). Patients with high-risk cytogenetics were distributed evenly across the three treatment arms.
The Rd continuous cohort also experienced significantly longer PFS, compared with the MPT arm (HR, 0.69, 95% CI, 0.59-0.79, P less than .00001).
“Taken together, these findings suggest that Rd affords a clinical advantage in subsequent lines of therapy and highlight the importance of using Rd continuous and not MPT as first-line treatment of transplant-ineligible patients with [newly-diagnosed multiple myeloma],” the researchers wrote.
The OS benefit was similar for patients who received Rd continuous (59.1 months) and Rd18 (62.3 months). The researchers suggested that the similar survival could be due to a combination of factors, including the impact of subsequent lines of treatment and the older age of the patient population.
However, the benefit for Rd18 was not seen in the PFS analysis. Patients in the Rd18 group had a median PFS similar to that of patients in the MPT group (21 months vs. 21.9 months), both of which were shorter than the Rd continuous group (26 months).
The 4-year PFS more than doubled among patients in the Rd continuous arm (32.6%), compared with patients in both the Rd18 group (14.3%) and the MPT group (13.6%).
Patients in the Rd continuous group also experienced a decreased risk for progression or death, compared with patients in the Rd18 group (HR, 0.70, 95% CI, 0.60-0.81).
The researchers noted that no new safety concerns were observed in the final analysis. Second primary malignancies, including hematologic and solid tumors, were found in 36% of patients in the Rd continuous group, 38% of patients in the Rd18 group, and 46% of patients in the MPT group.
Celgene Corporation sponsored the study. Dr. Facon and his coauthors reported financial ties to various pharmaceutical companies, including Celgene.
SOURCE: Facon T et al. Blood. 2018 Jan 18;131(3):301-10.
FROM BLOOD
Key clinical point:
Major finding: Continuously administered lenalidomide with dexamethasone regimen improved PFS (HR, 0.69) and OS (HR, 0.78), compared with melphalan, prednisone, and thalidomide.
Study details: Final analysis of the phase 3 FIRST trial.
Disclosures: Celgene Corporation sponsored the study. Dr. Facon and his coauthors reported financial ties to various pharmaceutical companies, including Celgene.
Source: Facon T et al. Blood. 2018 Jan 18;131(3):301-10.
FDG PET can’t replace BM biopsy, study suggests
LA JOLLA, CA—Fluorodeoxyglucose positron emission tomography (FDG PET) cannot replace bone marrow (BM) biopsy in T-cell lymphomas, according to a speaker at the 10th Annual T-cell Lymphoma Forum.
Researchers found that FDG PET results did not exactly correlate with BM biopsy results relating to tumor involvement in patients with T-cell lymphomas.
However, results from FDG PET were found to be an independent prognostic factor for progression-free survival (PFS) and overall survival (OS).
Youngil Koh, MD, of Seoul National University Hospital in Seoul, South Korea, presented this research in a poster and oral presentation at this year’s T-cell Lymphoma Forum.
He and his colleagues set out to investigate the clinical value of FDG PET for evaluating BM tumor involvement and prognosis in T-cell lymphoma patients.
The team analyzed 109 patients who underwent staging with FDG PET and BM biopsy. Most patients had extranodal natural killer/T-cell lymphoma, nasal type (NKTCL, n=46), or angioimmunoblastic T-cell lymphoma (AITL, n=41).
Patients also had peripheral T-cell lymphoma not otherwise specified (n=12), anaplastic large-cell lymphoma (n=4), enteropathy-associated T-cell lymphoma (n=4), and subcutaneous panniculitis-like T-cell lymphoma (n=2).
Most patients (87.2%) received chemotherapy as first-line treatment. Fifty percent were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like regimens, 48.1% were IMEP (ifosphamide, methotrexate, etoposide, and prednisolone) or IMEP-like regimens, and 1.9% were “other” regimens.
Other first-line treatments included radiotherapy followed by chemotherapy (10.1%), excision (0.9%), and no treatment (1.8%).
The patients’ median OS was 60.03 months, and the median PFS was 15.7 months.
BM involvement
The researchers analyzed PET BM uptake both visually and quantitatively using the marrow-to-liver ratio (MLR), and they compared these results to BM biopsy results.
According to BM biopsy, 35.8% of patients had tumor involvement.
By visual analysis, the sensitivity of PET for diagnosing positive BM biopsy was 58.5%, and the specificity was 77.9%. By MLR, the sensitivity was 64.1%, and the specificity was 72.9%.
The diagnostic performance of PET for BM involvement was not different across the lymphoma subtypes, Dr Koh said.
Prognosis
“Although FDG PET did not correlate very well with bone marrow biopsy, it had prognostic value, especially MLR,” Dr Koh noted. “And most importantly, in bone marrow biopsy-negative patients, it [MLR] had prognostic value.”
MLR was a significant prognostic factor for PFS (P=0.005) and OS (P<0.001). The same was true for BM biopsy (P=0.009 for PFS and P<0.001 for OS), while visual PET analysis was a significant prognostic factor for OS (P=0.015) but not PFS (P=0.476).
In patients negative by BM biopsy, MLR was a significant prognostic factor for PFS (P=0.001) and OS (P=0.005).
Dr Koh and his colleagues also analyzed the prognostic value of PET and BM biopsy specifically in patients with NKTCL and AITL.
In AITL patients, BM biopsy was a significant prognostic factor for OS (P=0.002) but not PFS (P=0.246). Visual PET analysis was not significant for PFS (P=0.910) or OS (P=0.581), and neither was MLR (P=0.053 for PFS and P=0.156 for OS).
In patients with NKTCL, BM biopsy was a significant prognostic factor for PFS (P=0.008) and OS (P<0.001). Visual PET analysis was not significant for PFS (P=0.469) or OS (P=0.092). And MLR was significant for PFS (P=0.004) and OS (P=0.012).
“Bone marrow findings of FDG PET are an independent prognostic factor in these tumors,” Dr Koh said, “suggesting the biologic relevance of FDG PET findings for aggressiveness or covert bone marrow involvement of tumor cells.”
LA JOLLA, CA—Fluorodeoxyglucose positron emission tomography (FDG PET) cannot replace bone marrow (BM) biopsy in T-cell lymphomas, according to a speaker at the 10th Annual T-cell Lymphoma Forum.
Researchers found that FDG PET results did not exactly correlate with BM biopsy results relating to tumor involvement in patients with T-cell lymphomas.
However, results from FDG PET were found to be an independent prognostic factor for progression-free survival (PFS) and overall survival (OS).
Youngil Koh, MD, of Seoul National University Hospital in Seoul, South Korea, presented this research in a poster and oral presentation at this year’s T-cell Lymphoma Forum.
He and his colleagues set out to investigate the clinical value of FDG PET for evaluating BM tumor involvement and prognosis in T-cell lymphoma patients.
The team analyzed 109 patients who underwent staging with FDG PET and BM biopsy. Most patients had extranodal natural killer/T-cell lymphoma, nasal type (NKTCL, n=46), or angioimmunoblastic T-cell lymphoma (AITL, n=41).
Patients also had peripheral T-cell lymphoma not otherwise specified (n=12), anaplastic large-cell lymphoma (n=4), enteropathy-associated T-cell lymphoma (n=4), and subcutaneous panniculitis-like T-cell lymphoma (n=2).
Most patients (87.2%) received chemotherapy as first-line treatment. Fifty percent were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like regimens, 48.1% were IMEP (ifosphamide, methotrexate, etoposide, and prednisolone) or IMEP-like regimens, and 1.9% were “other” regimens.
Other first-line treatments included radiotherapy followed by chemotherapy (10.1%), excision (0.9%), and no treatment (1.8%).
The patients’ median OS was 60.03 months, and the median PFS was 15.7 months.
BM involvement
The researchers analyzed PET BM uptake both visually and quantitatively using the marrow-to-liver ratio (MLR), and they compared these results to BM biopsy results.
According to BM biopsy, 35.8% of patients had tumor involvement.
By visual analysis, the sensitivity of PET for diagnosing positive BM biopsy was 58.5%, and the specificity was 77.9%. By MLR, the sensitivity was 64.1%, and the specificity was 72.9%.
The diagnostic performance of PET for BM involvement was not different across the lymphoma subtypes, Dr Koh said.
Prognosis
“Although FDG PET did not correlate very well with bone marrow biopsy, it had prognostic value, especially MLR,” Dr Koh noted. “And most importantly, in bone marrow biopsy-negative patients, it [MLR] had prognostic value.”
MLR was a significant prognostic factor for PFS (P=0.005) and OS (P<0.001). The same was true for BM biopsy (P=0.009 for PFS and P<0.001 for OS), while visual PET analysis was a significant prognostic factor for OS (P=0.015) but not PFS (P=0.476).
In patients negative by BM biopsy, MLR was a significant prognostic factor for PFS (P=0.001) and OS (P=0.005).
Dr Koh and his colleagues also analyzed the prognostic value of PET and BM biopsy specifically in patients with NKTCL and AITL.
In AITL patients, BM biopsy was a significant prognostic factor for OS (P=0.002) but not PFS (P=0.246). Visual PET analysis was not significant for PFS (P=0.910) or OS (P=0.581), and neither was MLR (P=0.053 for PFS and P=0.156 for OS).
In patients with NKTCL, BM biopsy was a significant prognostic factor for PFS (P=0.008) and OS (P<0.001). Visual PET analysis was not significant for PFS (P=0.469) or OS (P=0.092). And MLR was significant for PFS (P=0.004) and OS (P=0.012).
“Bone marrow findings of FDG PET are an independent prognostic factor in these tumors,” Dr Koh said, “suggesting the biologic relevance of FDG PET findings for aggressiveness or covert bone marrow involvement of tumor cells.”
LA JOLLA, CA—Fluorodeoxyglucose positron emission tomography (FDG PET) cannot replace bone marrow (BM) biopsy in T-cell lymphomas, according to a speaker at the 10th Annual T-cell Lymphoma Forum.
Researchers found that FDG PET results did not exactly correlate with BM biopsy results relating to tumor involvement in patients with T-cell lymphomas.
However, results from FDG PET were found to be an independent prognostic factor for progression-free survival (PFS) and overall survival (OS).
Youngil Koh, MD, of Seoul National University Hospital in Seoul, South Korea, presented this research in a poster and oral presentation at this year’s T-cell Lymphoma Forum.
He and his colleagues set out to investigate the clinical value of FDG PET for evaluating BM tumor involvement and prognosis in T-cell lymphoma patients.
The team analyzed 109 patients who underwent staging with FDG PET and BM biopsy. Most patients had extranodal natural killer/T-cell lymphoma, nasal type (NKTCL, n=46), or angioimmunoblastic T-cell lymphoma (AITL, n=41).
Patients also had peripheral T-cell lymphoma not otherwise specified (n=12), anaplastic large-cell lymphoma (n=4), enteropathy-associated T-cell lymphoma (n=4), and subcutaneous panniculitis-like T-cell lymphoma (n=2).
Most patients (87.2%) received chemotherapy as first-line treatment. Fifty percent were CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like regimens, 48.1% were IMEP (ifosphamide, methotrexate, etoposide, and prednisolone) or IMEP-like regimens, and 1.9% were “other” regimens.
Other first-line treatments included radiotherapy followed by chemotherapy (10.1%), excision (0.9%), and no treatment (1.8%).
The patients’ median OS was 60.03 months, and the median PFS was 15.7 months.
BM involvement
The researchers analyzed PET BM uptake both visually and quantitatively using the marrow-to-liver ratio (MLR), and they compared these results to BM biopsy results.
According to BM biopsy, 35.8% of patients had tumor involvement.
By visual analysis, the sensitivity of PET for diagnosing positive BM biopsy was 58.5%, and the specificity was 77.9%. By MLR, the sensitivity was 64.1%, and the specificity was 72.9%.
The diagnostic performance of PET for BM involvement was not different across the lymphoma subtypes, Dr Koh said.
Prognosis
“Although FDG PET did not correlate very well with bone marrow biopsy, it had prognostic value, especially MLR,” Dr Koh noted. “And most importantly, in bone marrow biopsy-negative patients, it [MLR] had prognostic value.”
MLR was a significant prognostic factor for PFS (P=0.005) and OS (P<0.001). The same was true for BM biopsy (P=0.009 for PFS and P<0.001 for OS), while visual PET analysis was a significant prognostic factor for OS (P=0.015) but not PFS (P=0.476).
In patients negative by BM biopsy, MLR was a significant prognostic factor for PFS (P=0.001) and OS (P=0.005).
Dr Koh and his colleagues also analyzed the prognostic value of PET and BM biopsy specifically in patients with NKTCL and AITL.
In AITL patients, BM biopsy was a significant prognostic factor for OS (P=0.002) but not PFS (P=0.246). Visual PET analysis was not significant for PFS (P=0.910) or OS (P=0.581), and neither was MLR (P=0.053 for PFS and P=0.156 for OS).
In patients with NKTCL, BM biopsy was a significant prognostic factor for PFS (P=0.008) and OS (P<0.001). Visual PET analysis was not significant for PFS (P=0.469) or OS (P=0.092). And MLR was significant for PFS (P=0.004) and OS (P=0.012).
“Bone marrow findings of FDG PET are an independent prognostic factor in these tumors,” Dr Koh said, “suggesting the biologic relevance of FDG PET findings for aggressiveness or covert bone marrow involvement of tumor cells.”
Inhibitor provides clinical improvement in MF
LA JOLLA, CA—Results of a phase 1 trial suggest MRG-106 can provide clinical improvement in patients with mycosis fungoides (MF), whether the drug is given alone or in conjunction with other therapies.
MRG-106 is an inhibitor of microRNA-155, which is upregulated in MF.
In this ongoing trial, 90% of patients who received MRG-106 have experienced an improvement in mSWAT score, and 59% of patients who received the drug for at least 1 month had a partial response.
The most common adverse events (AEs) attributed to MRG-106 were neutropenia, injection site pain, and fatigue.
Christiane Querfeld, MD, PhD, of the City of Hope in Duarte, California, presented these results at the 10th Annual T-cell Lymphoma Forum. The research is sponsored by miRagen Therapeutics, Inc., the company developing MRG-106.
The trial has enrolled 36 MF patients, 69% of whom are male. Their median age at enrollment was 63 (range, 21-85).
Patients had received a median of 4 prior systemic therapies (range, 1-13) and a median of 3 prior skin-directed therapies (range, 1-8).
At baseline, patients had a median mSWAT score of 43 (range, 2-180). The modified Severity Weighted Assessment Tool (mSWAT) measures the severity of skin disease over a patient’s body.
Part A
In part A of the study, 6 patients received MRG-106 via intralesional injection. A 75 mg dose of the drug was found to be well-tolerated, producing generally minor injection site reactions.
In addition, intralesional injection of MRG-106 produced improvements in CAILS score. The Composite Assessment of Index Lesion Severity (CAILS) score is obtained by adding the severity score of erythema, scaling, plaque elevation, and surface area for up to 5 index lesions.
Part B
In part B, 30 patients received MRG-106 via subcutaneous (SQ) injection, intravenous (IV) infusion, or IV bolus injection.
Patients who received SQ injection or IV infusion received doses of 300 mg, 600 mg, or 900 mg. Those who received an IV bolus only received the 300 mg dose.
Twenty-nine of the 30 patients in part B were evaluable for efficacy. Twenty-six of these patients—90%—had an improvement in mSWAT score from baseline.
“Twenty-six patients had at least stable disease to partial response,” Dr Querfeld noted. “No complete responses yet, but we’re close.”
Twelve patients were still receiving MRG-106 at last follow-up.
Ten of the 17 patients (59%) who had received MRG-106 for more than 1 month had at least a 50% improvement in mSWAT score, or a partial response. Once this was achieved, responses were durable.
One patient was still in response at roughly 470 days of follow-up.
Concomitant therapies
Dr Querfeld and her colleagues looked at patient outcomes in the context of concomitant therapies as well. They analyzed data from 26 patients who had received at least 6 doses of MRG-106.
Half of these patients were receiving MRG-106 alone, and the other half were receiving concomitant therapies, including bexarotene (n=7), interferon-alfa (n=2), methotrexate (n=1), vorinostat (n=1), and “other” treatments (n=2). Patients had been receiving these therapies for anywhere from 4 months to 45 months.
Outcomes were similar in the monotherapy and combination treatment groups. Seven patients in each group had at least a 50% improvement in mSWAT score.
Dosing and administration
“It appears the infusion is superior to the subcutaneous administration,” Dr Querfeld said.
She noted that durable partial responses have been achieved at all dose levels, but the 300 mg and 600 mg IV infusions had the best efficacy and tolerability profiles.
With the 300 mg IV bolus, fewer patients remained on treatment for more than 1 cycle, as compared to the other dosing cohorts. Dr Querfeld said this may be a result of lower total exposure or tolerability due to higher plasma Cmax.
She also noted that patients who received MRG-106 SQ at 600 mg or higher had a higher incidence of injection site reactions.
Safety
AEs of any grade that were attributed to MRG-106 include neutropenia (16%), injection site pain (16%), fatigue (14%), nausea (5%), pruritus (5%), and headache (5%).
Grade 3/4 AEs attributed to MRG-106 were neutropenia (5%) and pruritus (5%).
There were no serious AEs attributed to MRG-106, but there were 2 dose-limiting toxicities. One was a grade 3 tumor flare in a patient receiving the 300 mg IV bolus.
The other dose-limiting toxicity was grade 3 worsening pruritus and possible tumor flare, which occurred twice in 1 patient—with the 900 mg SQ dose and with the 300 mg IV infusion.
The 300 mg IV infusion is the anticipated phase 2 dose.
LA JOLLA, CA—Results of a phase 1 trial suggest MRG-106 can provide clinical improvement in patients with mycosis fungoides (MF), whether the drug is given alone or in conjunction with other therapies.
MRG-106 is an inhibitor of microRNA-155, which is upregulated in MF.
In this ongoing trial, 90% of patients who received MRG-106 have experienced an improvement in mSWAT score, and 59% of patients who received the drug for at least 1 month had a partial response.
The most common adverse events (AEs) attributed to MRG-106 were neutropenia, injection site pain, and fatigue.
Christiane Querfeld, MD, PhD, of the City of Hope in Duarte, California, presented these results at the 10th Annual T-cell Lymphoma Forum. The research is sponsored by miRagen Therapeutics, Inc., the company developing MRG-106.
The trial has enrolled 36 MF patients, 69% of whom are male. Their median age at enrollment was 63 (range, 21-85).
Patients had received a median of 4 prior systemic therapies (range, 1-13) and a median of 3 prior skin-directed therapies (range, 1-8).
At baseline, patients had a median mSWAT score of 43 (range, 2-180). The modified Severity Weighted Assessment Tool (mSWAT) measures the severity of skin disease over a patient’s body.
Part A
In part A of the study, 6 patients received MRG-106 via intralesional injection. A 75 mg dose of the drug was found to be well-tolerated, producing generally minor injection site reactions.
In addition, intralesional injection of MRG-106 produced improvements in CAILS score. The Composite Assessment of Index Lesion Severity (CAILS) score is obtained by adding the severity score of erythema, scaling, plaque elevation, and surface area for up to 5 index lesions.
Part B
In part B, 30 patients received MRG-106 via subcutaneous (SQ) injection, intravenous (IV) infusion, or IV bolus injection.
Patients who received SQ injection or IV infusion received doses of 300 mg, 600 mg, or 900 mg. Those who received an IV bolus only received the 300 mg dose.
Twenty-nine of the 30 patients in part B were evaluable for efficacy. Twenty-six of these patients—90%—had an improvement in mSWAT score from baseline.
“Twenty-six patients had at least stable disease to partial response,” Dr Querfeld noted. “No complete responses yet, but we’re close.”
Twelve patients were still receiving MRG-106 at last follow-up.
Ten of the 17 patients (59%) who had received MRG-106 for more than 1 month had at least a 50% improvement in mSWAT score, or a partial response. Once this was achieved, responses were durable.
One patient was still in response at roughly 470 days of follow-up.
Concomitant therapies
Dr Querfeld and her colleagues looked at patient outcomes in the context of concomitant therapies as well. They analyzed data from 26 patients who had received at least 6 doses of MRG-106.
Half of these patients were receiving MRG-106 alone, and the other half were receiving concomitant therapies, including bexarotene (n=7), interferon-alfa (n=2), methotrexate (n=1), vorinostat (n=1), and “other” treatments (n=2). Patients had been receiving these therapies for anywhere from 4 months to 45 months.
Outcomes were similar in the monotherapy and combination treatment groups. Seven patients in each group had at least a 50% improvement in mSWAT score.
Dosing and administration
“It appears the infusion is superior to the subcutaneous administration,” Dr Querfeld said.
She noted that durable partial responses have been achieved at all dose levels, but the 300 mg and 600 mg IV infusions had the best efficacy and tolerability profiles.
With the 300 mg IV bolus, fewer patients remained on treatment for more than 1 cycle, as compared to the other dosing cohorts. Dr Querfeld said this may be a result of lower total exposure or tolerability due to higher plasma Cmax.
She also noted that patients who received MRG-106 SQ at 600 mg or higher had a higher incidence of injection site reactions.
Safety
AEs of any grade that were attributed to MRG-106 include neutropenia (16%), injection site pain (16%), fatigue (14%), nausea (5%), pruritus (5%), and headache (5%).
Grade 3/4 AEs attributed to MRG-106 were neutropenia (5%) and pruritus (5%).
There were no serious AEs attributed to MRG-106, but there were 2 dose-limiting toxicities. One was a grade 3 tumor flare in a patient receiving the 300 mg IV bolus.
The other dose-limiting toxicity was grade 3 worsening pruritus and possible tumor flare, which occurred twice in 1 patient—with the 900 mg SQ dose and with the 300 mg IV infusion.
The 300 mg IV infusion is the anticipated phase 2 dose.
LA JOLLA, CA—Results of a phase 1 trial suggest MRG-106 can provide clinical improvement in patients with mycosis fungoides (MF), whether the drug is given alone or in conjunction with other therapies.
MRG-106 is an inhibitor of microRNA-155, which is upregulated in MF.
In this ongoing trial, 90% of patients who received MRG-106 have experienced an improvement in mSWAT score, and 59% of patients who received the drug for at least 1 month had a partial response.
The most common adverse events (AEs) attributed to MRG-106 were neutropenia, injection site pain, and fatigue.
Christiane Querfeld, MD, PhD, of the City of Hope in Duarte, California, presented these results at the 10th Annual T-cell Lymphoma Forum. The research is sponsored by miRagen Therapeutics, Inc., the company developing MRG-106.
The trial has enrolled 36 MF patients, 69% of whom are male. Their median age at enrollment was 63 (range, 21-85).
Patients had received a median of 4 prior systemic therapies (range, 1-13) and a median of 3 prior skin-directed therapies (range, 1-8).
At baseline, patients had a median mSWAT score of 43 (range, 2-180). The modified Severity Weighted Assessment Tool (mSWAT) measures the severity of skin disease over a patient’s body.
Part A
In part A of the study, 6 patients received MRG-106 via intralesional injection. A 75 mg dose of the drug was found to be well-tolerated, producing generally minor injection site reactions.
In addition, intralesional injection of MRG-106 produced improvements in CAILS score. The Composite Assessment of Index Lesion Severity (CAILS) score is obtained by adding the severity score of erythema, scaling, plaque elevation, and surface area for up to 5 index lesions.
Part B
In part B, 30 patients received MRG-106 via subcutaneous (SQ) injection, intravenous (IV) infusion, or IV bolus injection.
Patients who received SQ injection or IV infusion received doses of 300 mg, 600 mg, or 900 mg. Those who received an IV bolus only received the 300 mg dose.
Twenty-nine of the 30 patients in part B were evaluable for efficacy. Twenty-six of these patients—90%—had an improvement in mSWAT score from baseline.
“Twenty-six patients had at least stable disease to partial response,” Dr Querfeld noted. “No complete responses yet, but we’re close.”
Twelve patients were still receiving MRG-106 at last follow-up.
Ten of the 17 patients (59%) who had received MRG-106 for more than 1 month had at least a 50% improvement in mSWAT score, or a partial response. Once this was achieved, responses were durable.
One patient was still in response at roughly 470 days of follow-up.
Concomitant therapies
Dr Querfeld and her colleagues looked at patient outcomes in the context of concomitant therapies as well. They analyzed data from 26 patients who had received at least 6 doses of MRG-106.
Half of these patients were receiving MRG-106 alone, and the other half were receiving concomitant therapies, including bexarotene (n=7), interferon-alfa (n=2), methotrexate (n=1), vorinostat (n=1), and “other” treatments (n=2). Patients had been receiving these therapies for anywhere from 4 months to 45 months.
Outcomes were similar in the monotherapy and combination treatment groups. Seven patients in each group had at least a 50% improvement in mSWAT score.
Dosing and administration
“It appears the infusion is superior to the subcutaneous administration,” Dr Querfeld said.
She noted that durable partial responses have been achieved at all dose levels, but the 300 mg and 600 mg IV infusions had the best efficacy and tolerability profiles.
With the 300 mg IV bolus, fewer patients remained on treatment for more than 1 cycle, as compared to the other dosing cohorts. Dr Querfeld said this may be a result of lower total exposure or tolerability due to higher plasma Cmax.
She also noted that patients who received MRG-106 SQ at 600 mg or higher had a higher incidence of injection site reactions.
Safety
AEs of any grade that were attributed to MRG-106 include neutropenia (16%), injection site pain (16%), fatigue (14%), nausea (5%), pruritus (5%), and headache (5%).
Grade 3/4 AEs attributed to MRG-106 were neutropenia (5%) and pruritus (5%).
There were no serious AEs attributed to MRG-106, but there were 2 dose-limiting toxicities. One was a grade 3 tumor flare in a patient receiving the 300 mg IV bolus.
The other dose-limiting toxicity was grade 3 worsening pruritus and possible tumor flare, which occurred twice in 1 patient—with the 900 mg SQ dose and with the 300 mg IV infusion.
The 300 mg IV infusion is the anticipated phase 2 dose.
T-cell lymphoma therapies on the horizon
LA JOLLA, CALIF. – There are several biologic compounds in early clinical development for treatment of patients with T-cell lymphomas, including an antibody-drug conjugate, novel immune checkpoint inhibitor, and bi-specific antibody.
These investigational agents show promising single-agent activity and have the potential to improve clinical responses when combined with combination chemotherapy regimens or other treatments, Ahmed Sawas, MD, of the Center for Lymphoid Malignancies at Columbia University, New York, said at the annual T-cell Lymphoma Forum.
AGS67E: Antibody-drug conjugate
AGS67E is an antibody-drug conjugate targeted against CD37, a transmembrane protein preferentially expressed on malignant B cells, T cells, and acute myeloid leukemia cells. In a study published in 2015 in Molecular Cancer Therapeutics, investigators from Agensys (an affiliate of Astellas Pharma) reported that this compound bound to more than 80% of patient-derived T cells in vitro (Mol Cancer Ther. 2015;14[7]:1650-60).
In a phase 1 dose-escalation study reported at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, Dr. Sawas and his colleagues found that patients with B-cell and T-cell malignancies, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, tolerated the drug well when it was delivered both with or without growth factor. Neutropenia was the most frequent adverse event and dose-limiting toxicity.
The drug showed single-agent activity in 16 of 53 patients with heavily pretreated non-Hodgkin lymphoma, including a partial response in one of two patients with cutaneous T-cell lymphoma, and partial responses in two of four patients with peripheral T-cell lymphoma. There were no complete responses at any of three dose levels of the drug, with or without growth factor.
One patient, a 75-year-old man with stage IVB mycosis fungoides who had disease progression on prior therapy with methotrexate, romidepsin, bendamustine, whole-body irradiation, liposomal doxorubicin, pralatrexate, and pembrolizumab experienced significant reduction in tumor burden and resolution of lymph node involvement after three 3-week cycles of therapy with AGS67E. The patient had a deepening of the response with additional cycles, and remained on therapy for 30 cycles until he experienced disease progression.
TTI-621: Tuck in, macrophages
TT1-621 is a molecule with two functions: It acts as an immune checkpoint inhibitor by blocking CD47, which binds to signal-regulatory protein alpha to produce an antiphagocytic or “do not eat” signal. TTI-621 does not, however, bind to CD47-positive erythrocytes.
In addition to blocking CD47 and the do-not-eat signal, TTI-621 delivers an activating signal to macrophages through Fc gamma receptors, telling them, in effect, “bon appétit.”
In a study presented at the 2017 annual meeting of the American Society of Hematology (Abstract 4076), investigators from City of Hope in Duarte, Calif., and other centers reported that a single direct intratumoral injection of TTI-621 was associated with significant antitumor activity in patients with relapsed or refractory mycosis fungoides and Sézary syndrome, with one of nine patients having a complete response in the injected lesion, and five having decreases in tumor size and/or circulating Sézary cells.
Patients appeared to tolerate this agent very well, with 1 of 18 having a grade 3 increase in white blood cell count. The most commonly reported side effects were fatigue, chills, decreased appetite, headache, injection site pain, and generalized pruritus, each occurring in 3 of the 18 patients.
TTI-621 injection was associated with rapid declines in Composite Assessment of Index Lesion Severity scores in dose-finding studies in patients with heavily pretreated cutaneous T-cell lymphoma, Dr. Sawas said.
AFM13: Two for the price of one
AFM13 is a bi-specific antibody that binds to CD30, which is expressed on anaplastic large cell lymphoma cells, as well as Reed-Sternberg cells of classical Hodgkin lymphoma. This antibody also engages CD16A-positive cells, resulting in lysis of CD30-positive tumor cells. It is a specific recruiter of natural killer cells, and does not bind to neutrophils.
In an early biologic effects study of this agent in CD30-positive lymphoid malignancies with cutaneous presentation, Dr. Sawas and his colleagues observed an early response and regression of cutaneous anaplastic large cell lymphoma lesions in a heavily pretreated patient, with progression occurring when the patient went off therapy, and tumors that diminished on reinitiation of therapy that sustained beyond a second discontinuation of therapy. This patient had measurable reductions in lymphoma burden on PET CT scans and improvements in cutaneous lesions. Dr. Sawas did not present safety data for this agent.
AGS67E studies are supported by Agensys. TTI-621 studies are supported by Trillium Therapeutics. The AFM13 study is supported by Columbia University, with Dr. Sawas listed as the sponsor. He did not report potential conflicts of interests. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – There are several biologic compounds in early clinical development for treatment of patients with T-cell lymphomas, including an antibody-drug conjugate, novel immune checkpoint inhibitor, and bi-specific antibody.
These investigational agents show promising single-agent activity and have the potential to improve clinical responses when combined with combination chemotherapy regimens or other treatments, Ahmed Sawas, MD, of the Center for Lymphoid Malignancies at Columbia University, New York, said at the annual T-cell Lymphoma Forum.
AGS67E: Antibody-drug conjugate
AGS67E is an antibody-drug conjugate targeted against CD37, a transmembrane protein preferentially expressed on malignant B cells, T cells, and acute myeloid leukemia cells. In a study published in 2015 in Molecular Cancer Therapeutics, investigators from Agensys (an affiliate of Astellas Pharma) reported that this compound bound to more than 80% of patient-derived T cells in vitro (Mol Cancer Ther. 2015;14[7]:1650-60).
In a phase 1 dose-escalation study reported at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, Dr. Sawas and his colleagues found that patients with B-cell and T-cell malignancies, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, tolerated the drug well when it was delivered both with or without growth factor. Neutropenia was the most frequent adverse event and dose-limiting toxicity.
The drug showed single-agent activity in 16 of 53 patients with heavily pretreated non-Hodgkin lymphoma, including a partial response in one of two patients with cutaneous T-cell lymphoma, and partial responses in two of four patients with peripheral T-cell lymphoma. There were no complete responses at any of three dose levels of the drug, with or without growth factor.
One patient, a 75-year-old man with stage IVB mycosis fungoides who had disease progression on prior therapy with methotrexate, romidepsin, bendamustine, whole-body irradiation, liposomal doxorubicin, pralatrexate, and pembrolizumab experienced significant reduction in tumor burden and resolution of lymph node involvement after three 3-week cycles of therapy with AGS67E. The patient had a deepening of the response with additional cycles, and remained on therapy for 30 cycles until he experienced disease progression.
TTI-621: Tuck in, macrophages
TT1-621 is a molecule with two functions: It acts as an immune checkpoint inhibitor by blocking CD47, which binds to signal-regulatory protein alpha to produce an antiphagocytic or “do not eat” signal. TTI-621 does not, however, bind to CD47-positive erythrocytes.
In addition to blocking CD47 and the do-not-eat signal, TTI-621 delivers an activating signal to macrophages through Fc gamma receptors, telling them, in effect, “bon appétit.”
In a study presented at the 2017 annual meeting of the American Society of Hematology (Abstract 4076), investigators from City of Hope in Duarte, Calif., and other centers reported that a single direct intratumoral injection of TTI-621 was associated with significant antitumor activity in patients with relapsed or refractory mycosis fungoides and Sézary syndrome, with one of nine patients having a complete response in the injected lesion, and five having decreases in tumor size and/or circulating Sézary cells.
Patients appeared to tolerate this agent very well, with 1 of 18 having a grade 3 increase in white blood cell count. The most commonly reported side effects were fatigue, chills, decreased appetite, headache, injection site pain, and generalized pruritus, each occurring in 3 of the 18 patients.
TTI-621 injection was associated with rapid declines in Composite Assessment of Index Lesion Severity scores in dose-finding studies in patients with heavily pretreated cutaneous T-cell lymphoma, Dr. Sawas said.
AFM13: Two for the price of one
AFM13 is a bi-specific antibody that binds to CD30, which is expressed on anaplastic large cell lymphoma cells, as well as Reed-Sternberg cells of classical Hodgkin lymphoma. This antibody also engages CD16A-positive cells, resulting in lysis of CD30-positive tumor cells. It is a specific recruiter of natural killer cells, and does not bind to neutrophils.
In an early biologic effects study of this agent in CD30-positive lymphoid malignancies with cutaneous presentation, Dr. Sawas and his colleagues observed an early response and regression of cutaneous anaplastic large cell lymphoma lesions in a heavily pretreated patient, with progression occurring when the patient went off therapy, and tumors that diminished on reinitiation of therapy that sustained beyond a second discontinuation of therapy. This patient had measurable reductions in lymphoma burden on PET CT scans and improvements in cutaneous lesions. Dr. Sawas did not present safety data for this agent.
AGS67E studies are supported by Agensys. TTI-621 studies are supported by Trillium Therapeutics. The AFM13 study is supported by Columbia University, with Dr. Sawas listed as the sponsor. He did not report potential conflicts of interests. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
LA JOLLA, CALIF. – There are several biologic compounds in early clinical development for treatment of patients with T-cell lymphomas, including an antibody-drug conjugate, novel immune checkpoint inhibitor, and bi-specific antibody.
These investigational agents show promising single-agent activity and have the potential to improve clinical responses when combined with combination chemotherapy regimens or other treatments, Ahmed Sawas, MD, of the Center for Lymphoid Malignancies at Columbia University, New York, said at the annual T-cell Lymphoma Forum.
AGS67E: Antibody-drug conjugate
AGS67E is an antibody-drug conjugate targeted against CD37, a transmembrane protein preferentially expressed on malignant B cells, T cells, and acute myeloid leukemia cells. In a study published in 2015 in Molecular Cancer Therapeutics, investigators from Agensys (an affiliate of Astellas Pharma) reported that this compound bound to more than 80% of patient-derived T cells in vitro (Mol Cancer Ther. 2015;14[7]:1650-60).
In a phase 1 dose-escalation study reported at the 2017 International Conference on Malignant Lymphoma in Lugano, Switzerland, Dr. Sawas and his colleagues found that patients with B-cell and T-cell malignancies, including cutaneous T-cell lymphoma and peripheral T-cell lymphoma, tolerated the drug well when it was delivered both with or without growth factor. Neutropenia was the most frequent adverse event and dose-limiting toxicity.
The drug showed single-agent activity in 16 of 53 patients with heavily pretreated non-Hodgkin lymphoma, including a partial response in one of two patients with cutaneous T-cell lymphoma, and partial responses in two of four patients with peripheral T-cell lymphoma. There were no complete responses at any of three dose levels of the drug, with or without growth factor.
One patient, a 75-year-old man with stage IVB mycosis fungoides who had disease progression on prior therapy with methotrexate, romidepsin, bendamustine, whole-body irradiation, liposomal doxorubicin, pralatrexate, and pembrolizumab experienced significant reduction in tumor burden and resolution of lymph node involvement after three 3-week cycles of therapy with AGS67E. The patient had a deepening of the response with additional cycles, and remained on therapy for 30 cycles until he experienced disease progression.
TTI-621: Tuck in, macrophages
TT1-621 is a molecule with two functions: It acts as an immune checkpoint inhibitor by blocking CD47, which binds to signal-regulatory protein alpha to produce an antiphagocytic or “do not eat” signal. TTI-621 does not, however, bind to CD47-positive erythrocytes.
In addition to blocking CD47 and the do-not-eat signal, TTI-621 delivers an activating signal to macrophages through Fc gamma receptors, telling them, in effect, “bon appétit.”
In a study presented at the 2017 annual meeting of the American Society of Hematology (Abstract 4076), investigators from City of Hope in Duarte, Calif., and other centers reported that a single direct intratumoral injection of TTI-621 was associated with significant antitumor activity in patients with relapsed or refractory mycosis fungoides and Sézary syndrome, with one of nine patients having a complete response in the injected lesion, and five having decreases in tumor size and/or circulating Sézary cells.
Patients appeared to tolerate this agent very well, with 1 of 18 having a grade 3 increase in white blood cell count. The most commonly reported side effects were fatigue, chills, decreased appetite, headache, injection site pain, and generalized pruritus, each occurring in 3 of the 18 patients.
TTI-621 injection was associated with rapid declines in Composite Assessment of Index Lesion Severity scores in dose-finding studies in patients with heavily pretreated cutaneous T-cell lymphoma, Dr. Sawas said.
AFM13: Two for the price of one
AFM13 is a bi-specific antibody that binds to CD30, which is expressed on anaplastic large cell lymphoma cells, as well as Reed-Sternberg cells of classical Hodgkin lymphoma. This antibody also engages CD16A-positive cells, resulting in lysis of CD30-positive tumor cells. It is a specific recruiter of natural killer cells, and does not bind to neutrophils.
In an early biologic effects study of this agent in CD30-positive lymphoid malignancies with cutaneous presentation, Dr. Sawas and his colleagues observed an early response and regression of cutaneous anaplastic large cell lymphoma lesions in a heavily pretreated patient, with progression occurring when the patient went off therapy, and tumors that diminished on reinitiation of therapy that sustained beyond a second discontinuation of therapy. This patient had measurable reductions in lymphoma burden on PET CT scans and improvements in cutaneous lesions. Dr. Sawas did not present safety data for this agent.
AGS67E studies are supported by Agensys. TTI-621 studies are supported by Trillium Therapeutics. The AFM13 study is supported by Columbia University, with Dr. Sawas listed as the sponsor. He did not report potential conflicts of interests. The T-Cell Lymphoma Forum is held by Jonathan Wood & Associates, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM TCLF 2018
Drug may be option for B- and T-cell lymphomas
LA JOLLA, CA—The EZH1/2 inhibitor DS-3201b could be a novel therapeutic option for non-Hodgkin lymphoma (NHL), according to a speaker at the 10th Annual T-cell Lymphoma Forum.
DS-3201b was considered well tolerated in a phase 1 study of Japanese patients with relapsed/refractory NHL.
In addition, DS-3201b demonstrated activity against B- and T-cell lymphomas, producing an overall response rate of 59%.
Kunihiro Tsukasaki, MD, PhD, of Saitama Medical University in Moroyama, Saitama, Japan, presented these results at the meeting.
The trial was sponsored by Daiichi Sankyo Co., Ltd.
Dr Tsukasaki presented data on 18 patients with relapsed/refractory NHL.
The 12 B-cell lymphoma patients had follicular lymphoma (n=5), diffuse large B-cell lymphoma (n=3), MALT lymphoma (n=2), nodal marginal zone lymphoma (n=1), and lymphoplasmacytic lymphoma (n=1).
The 6 patients with T-cell lymphoma had peripheral T-cell lymphoma not otherwise specified (n=2), angioimmunoblastic T-cell lymphoma (n=2), and adult T-cell leukemia/lymphoma (n=2).
The patients’ median age was 67 (range, 44-75), and 10 were female. All patients had an ECOG performance status of 0 (72%) or 1 (28%).
Patients had a median of 2 prior chemotherapy regimens (range, 1-8).
For this study, they received DS-3201b at 150 mg (n=7), 200 mg (n=9), or 300 mg (n=2). They received the drug once daily in 28-day cycles until they progressed or experienced unacceptable toxicity.
DLTs and AEs
Dose-limiting toxicities (DLTs) were evaluated in cycle 1. All 18 patients were evaluable for DLT assessment.
There were 4 treatment-emergent adverse events (AEs) that met the definition of DLTs:
- 3 cases of grade 4 platelet count decrease (n=1 at 200 mg, n=2 at 300 mg)
- 1 case of grade 3 anemia requiring blood transfusion (at 300 mg).
All 4 DLTs led to treatment interruption.
There were 5 serious AEs reported in 3 patients. Only one of these—pneumocystis jiroveci pneumonia—was considered related to DS-3201b.
Hematologic AEs included decreases in platelets (grade 1-4), lymphocytes (grade 1-4), neutrophils (grade 2-4), and white blood cells (grade 2-3), as well as anemia (grade 1-3).
Other AEs (all grade 1/2) included dysgeusia, alopecia, diarrhea, decreased appetite, alanine aminotransferase increase, aspartate aminotransferase increase, nasopharyngitis, rash, and dry skin.
No deaths had been reported as of the data cutoff last November.
Responses
Seventeen patients were evaluable for response.
The overall response rate was 59%, with 1 patient achieving a complete response (CR) and 9 achieving a partial response (PR). Four patients had stable disease (SD), and 3 progressed.
Among the T-cell lymphoma patients, 1 had a CR, 4 had PRs, and 1 progressed. The complete responder had angioimmunoblastic T-cell lymphoma, and the patient who progressed had adult T-cell leukemia/lymphoma.
Among the B-cell lymphoma patients, 5 had PRs, 4 had SD, and 2 progressed.
Dr Tsukasaki said DS-3201b has demonstrated early clinical activity and therefore has the potential to be a novel therapeutic option for B-cell and T-cell lymphomas. However, further evaluation is warranted to determine the optimal dosing regimen and target diseases.
LA JOLLA, CA—The EZH1/2 inhibitor DS-3201b could be a novel therapeutic option for non-Hodgkin lymphoma (NHL), according to a speaker at the 10th Annual T-cell Lymphoma Forum.
DS-3201b was considered well tolerated in a phase 1 study of Japanese patients with relapsed/refractory NHL.
In addition, DS-3201b demonstrated activity against B- and T-cell lymphomas, producing an overall response rate of 59%.
Kunihiro Tsukasaki, MD, PhD, of Saitama Medical University in Moroyama, Saitama, Japan, presented these results at the meeting.
The trial was sponsored by Daiichi Sankyo Co., Ltd.
Dr Tsukasaki presented data on 18 patients with relapsed/refractory NHL.
The 12 B-cell lymphoma patients had follicular lymphoma (n=5), diffuse large B-cell lymphoma (n=3), MALT lymphoma (n=2), nodal marginal zone lymphoma (n=1), and lymphoplasmacytic lymphoma (n=1).
The 6 patients with T-cell lymphoma had peripheral T-cell lymphoma not otherwise specified (n=2), angioimmunoblastic T-cell lymphoma (n=2), and adult T-cell leukemia/lymphoma (n=2).
The patients’ median age was 67 (range, 44-75), and 10 were female. All patients had an ECOG performance status of 0 (72%) or 1 (28%).
Patients had a median of 2 prior chemotherapy regimens (range, 1-8).
For this study, they received DS-3201b at 150 mg (n=7), 200 mg (n=9), or 300 mg (n=2). They received the drug once daily in 28-day cycles until they progressed or experienced unacceptable toxicity.
DLTs and AEs
Dose-limiting toxicities (DLTs) were evaluated in cycle 1. All 18 patients were evaluable for DLT assessment.
There were 4 treatment-emergent adverse events (AEs) that met the definition of DLTs:
- 3 cases of grade 4 platelet count decrease (n=1 at 200 mg, n=2 at 300 mg)
- 1 case of grade 3 anemia requiring blood transfusion (at 300 mg).
All 4 DLTs led to treatment interruption.
There were 5 serious AEs reported in 3 patients. Only one of these—pneumocystis jiroveci pneumonia—was considered related to DS-3201b.
Hematologic AEs included decreases in platelets (grade 1-4), lymphocytes (grade 1-4), neutrophils (grade 2-4), and white blood cells (grade 2-3), as well as anemia (grade 1-3).
Other AEs (all grade 1/2) included dysgeusia, alopecia, diarrhea, decreased appetite, alanine aminotransferase increase, aspartate aminotransferase increase, nasopharyngitis, rash, and dry skin.
No deaths had been reported as of the data cutoff last November.
Responses
Seventeen patients were evaluable for response.
The overall response rate was 59%, with 1 patient achieving a complete response (CR) and 9 achieving a partial response (PR). Four patients had stable disease (SD), and 3 progressed.
Among the T-cell lymphoma patients, 1 had a CR, 4 had PRs, and 1 progressed. The complete responder had angioimmunoblastic T-cell lymphoma, and the patient who progressed had adult T-cell leukemia/lymphoma.
Among the B-cell lymphoma patients, 5 had PRs, 4 had SD, and 2 progressed.
Dr Tsukasaki said DS-3201b has demonstrated early clinical activity and therefore has the potential to be a novel therapeutic option for B-cell and T-cell lymphomas. However, further evaluation is warranted to determine the optimal dosing regimen and target diseases.
LA JOLLA, CA—The EZH1/2 inhibitor DS-3201b could be a novel therapeutic option for non-Hodgkin lymphoma (NHL), according to a speaker at the 10th Annual T-cell Lymphoma Forum.
DS-3201b was considered well tolerated in a phase 1 study of Japanese patients with relapsed/refractory NHL.
In addition, DS-3201b demonstrated activity against B- and T-cell lymphomas, producing an overall response rate of 59%.
Kunihiro Tsukasaki, MD, PhD, of Saitama Medical University in Moroyama, Saitama, Japan, presented these results at the meeting.
The trial was sponsored by Daiichi Sankyo Co., Ltd.
Dr Tsukasaki presented data on 18 patients with relapsed/refractory NHL.
The 12 B-cell lymphoma patients had follicular lymphoma (n=5), diffuse large B-cell lymphoma (n=3), MALT lymphoma (n=2), nodal marginal zone lymphoma (n=1), and lymphoplasmacytic lymphoma (n=1).
The 6 patients with T-cell lymphoma had peripheral T-cell lymphoma not otherwise specified (n=2), angioimmunoblastic T-cell lymphoma (n=2), and adult T-cell leukemia/lymphoma (n=2).
The patients’ median age was 67 (range, 44-75), and 10 were female. All patients had an ECOG performance status of 0 (72%) or 1 (28%).
Patients had a median of 2 prior chemotherapy regimens (range, 1-8).
For this study, they received DS-3201b at 150 mg (n=7), 200 mg (n=9), or 300 mg (n=2). They received the drug once daily in 28-day cycles until they progressed or experienced unacceptable toxicity.
DLTs and AEs
Dose-limiting toxicities (DLTs) were evaluated in cycle 1. All 18 patients were evaluable for DLT assessment.
There were 4 treatment-emergent adverse events (AEs) that met the definition of DLTs:
- 3 cases of grade 4 platelet count decrease (n=1 at 200 mg, n=2 at 300 mg)
- 1 case of grade 3 anemia requiring blood transfusion (at 300 mg).
All 4 DLTs led to treatment interruption.
There were 5 serious AEs reported in 3 patients. Only one of these—pneumocystis jiroveci pneumonia—was considered related to DS-3201b.
Hematologic AEs included decreases in platelets (grade 1-4), lymphocytes (grade 1-4), neutrophils (grade 2-4), and white blood cells (grade 2-3), as well as anemia (grade 1-3).
Other AEs (all grade 1/2) included dysgeusia, alopecia, diarrhea, decreased appetite, alanine aminotransferase increase, aspartate aminotransferase increase, nasopharyngitis, rash, and dry skin.
No deaths had been reported as of the data cutoff last November.
Responses
Seventeen patients were evaluable for response.
The overall response rate was 59%, with 1 patient achieving a complete response (CR) and 9 achieving a partial response (PR). Four patients had stable disease (SD), and 3 progressed.
Among the T-cell lymphoma patients, 1 had a CR, 4 had PRs, and 1 progressed. The complete responder had angioimmunoblastic T-cell lymphoma, and the patient who progressed had adult T-cell leukemia/lymphoma.
Among the B-cell lymphoma patients, 5 had PRs, 4 had SD, and 2 progressed.
Dr Tsukasaki said DS-3201b has demonstrated early clinical activity and therefore has the potential to be a novel therapeutic option for B-cell and T-cell lymphomas. However, further evaluation is warranted to determine the optimal dosing regimen and target diseases.
Assay identifies actionable mutations in lymphoid malignancies
Researchers say hybrid capture sequencing is an accurate and sensitive method for identifying actionable gene mutations in lymphoid malignancies.
This method revealed potentially actionable mutations in 91% of patients studied, who had diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or chronic lymphocytic leukemia (CLL).
The researchers therefore believe hybrid capture sequencing will bring the benefits of precision diagnosis and individualized therapy to patients with lymphoid malignancies.
“To realize the benefits of the most recent progress in cancer genomics, clinical implementation of precision medicine approaches is needed in the form of novel biomarker assays,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver, Canada.
“Fully implemented targeted sequencing-based assays in routine diagnostic pathology laboratories are currently lacking in lymphoid cancer care. Our findings demonstrate the feasibility and outline the clinical utility of integrating a lymphoma-specific pipeline into personalized cancer care.”
Dr Steidl and his colleagues reported these findings in The Journal of Molecular Diagnostics.
The researchers first compared capture hybridization and amplicon sequencing using samples from 8 patients with lymphoma. Fresh-frozen and formalin-fixed, paraffin-embedded tumor samples were sequenced using a panel of 20 lymphoma-specific genes.
The team found that capture hybridization provided “deep, more uniform coverage” and yielded “higher sensitivity for variant calling” than amplicon sequencing.
The researchers then developed a targeted sequencing pipeline using a 32-gene panel. The panel was developed with input from a group of 6 specialists who kept updating it based on the latest available information.
“This allows for continuous integration of additional gene features as our knowledge base improves,” Dr Steidl noted.
He and his colleagues then applied the hybrid capture sequencing assay and 32-gene panel to tissues from 219 patients—114 with FL, 76 with DLBCL, and 29 with CLL—who were treated in British Columbia between 2013 and 2016.
Results revealed at least one actionable mutation in 91% of the tumors. And the assay uncovered subtype-specific mutational profiles that were highly similar to published mutational profiles for FL, DLBCL, and CLL.
Furthermore, the assay had 93% concordance with whole-genome sequencing.
“Our developed assay harnesses the power of modern sequencing for clinical diagnostics purposes and potentially better deployment of novel treatments in lymphoid cancers,” Dr Steidl said. “We believe our study will help establish evidence-based approaches to decision making in lymphoid cancer care.”
“The next steps are to implement sequencing-based biomarker assays, such as reported in our study, in accredited pathology laboratories. Toward the goal of biomarker-driven clinical decision making, testing of potentially predictive biomarker assays is needed alongside clinical trials investigating novel cancer therapeutics.”
Researchers say hybrid capture sequencing is an accurate and sensitive method for identifying actionable gene mutations in lymphoid malignancies.
This method revealed potentially actionable mutations in 91% of patients studied, who had diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or chronic lymphocytic leukemia (CLL).
The researchers therefore believe hybrid capture sequencing will bring the benefits of precision diagnosis and individualized therapy to patients with lymphoid malignancies.
“To realize the benefits of the most recent progress in cancer genomics, clinical implementation of precision medicine approaches is needed in the form of novel biomarker assays,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver, Canada.
“Fully implemented targeted sequencing-based assays in routine diagnostic pathology laboratories are currently lacking in lymphoid cancer care. Our findings demonstrate the feasibility and outline the clinical utility of integrating a lymphoma-specific pipeline into personalized cancer care.”
Dr Steidl and his colleagues reported these findings in The Journal of Molecular Diagnostics.
The researchers first compared capture hybridization and amplicon sequencing using samples from 8 patients with lymphoma. Fresh-frozen and formalin-fixed, paraffin-embedded tumor samples were sequenced using a panel of 20 lymphoma-specific genes.
The team found that capture hybridization provided “deep, more uniform coverage” and yielded “higher sensitivity for variant calling” than amplicon sequencing.
The researchers then developed a targeted sequencing pipeline using a 32-gene panel. The panel was developed with input from a group of 6 specialists who kept updating it based on the latest available information.
“This allows for continuous integration of additional gene features as our knowledge base improves,” Dr Steidl noted.
He and his colleagues then applied the hybrid capture sequencing assay and 32-gene panel to tissues from 219 patients—114 with FL, 76 with DLBCL, and 29 with CLL—who were treated in British Columbia between 2013 and 2016.
Results revealed at least one actionable mutation in 91% of the tumors. And the assay uncovered subtype-specific mutational profiles that were highly similar to published mutational profiles for FL, DLBCL, and CLL.
Furthermore, the assay had 93% concordance with whole-genome sequencing.
“Our developed assay harnesses the power of modern sequencing for clinical diagnostics purposes and potentially better deployment of novel treatments in lymphoid cancers,” Dr Steidl said. “We believe our study will help establish evidence-based approaches to decision making in lymphoid cancer care.”
“The next steps are to implement sequencing-based biomarker assays, such as reported in our study, in accredited pathology laboratories. Toward the goal of biomarker-driven clinical decision making, testing of potentially predictive biomarker assays is needed alongside clinical trials investigating novel cancer therapeutics.”
Researchers say hybrid capture sequencing is an accurate and sensitive method for identifying actionable gene mutations in lymphoid malignancies.
This method revealed potentially actionable mutations in 91% of patients studied, who had diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or chronic lymphocytic leukemia (CLL).
The researchers therefore believe hybrid capture sequencing will bring the benefits of precision diagnosis and individualized therapy to patients with lymphoid malignancies.
“To realize the benefits of the most recent progress in cancer genomics, clinical implementation of precision medicine approaches is needed in the form of novel biomarker assays,” said study author Christian Steidl, MD, of the University of British Columbia in Vancouver, Canada.
“Fully implemented targeted sequencing-based assays in routine diagnostic pathology laboratories are currently lacking in lymphoid cancer care. Our findings demonstrate the feasibility and outline the clinical utility of integrating a lymphoma-specific pipeline into personalized cancer care.”
Dr Steidl and his colleagues reported these findings in The Journal of Molecular Diagnostics.
The researchers first compared capture hybridization and amplicon sequencing using samples from 8 patients with lymphoma. Fresh-frozen and formalin-fixed, paraffin-embedded tumor samples were sequenced using a panel of 20 lymphoma-specific genes.
The team found that capture hybridization provided “deep, more uniform coverage” and yielded “higher sensitivity for variant calling” than amplicon sequencing.
The researchers then developed a targeted sequencing pipeline using a 32-gene panel. The panel was developed with input from a group of 6 specialists who kept updating it based on the latest available information.
“This allows for continuous integration of additional gene features as our knowledge base improves,” Dr Steidl noted.
He and his colleagues then applied the hybrid capture sequencing assay and 32-gene panel to tissues from 219 patients—114 with FL, 76 with DLBCL, and 29 with CLL—who were treated in British Columbia between 2013 and 2016.
Results revealed at least one actionable mutation in 91% of the tumors. And the assay uncovered subtype-specific mutational profiles that were highly similar to published mutational profiles for FL, DLBCL, and CLL.
Furthermore, the assay had 93% concordance with whole-genome sequencing.
“Our developed assay harnesses the power of modern sequencing for clinical diagnostics purposes and potentially better deployment of novel treatments in lymphoid cancers,” Dr Steidl said. “We believe our study will help establish evidence-based approaches to decision making in lymphoid cancer care.”
“The next steps are to implement sequencing-based biomarker assays, such as reported in our study, in accredited pathology laboratories. Toward the goal of biomarker-driven clinical decision making, testing of potentially predictive biomarker assays is needed alongside clinical trials investigating novel cancer therapeutics.”