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Inhibitor may overcome ibrutinib resistance in MCL
Investigators have identified a mechanism of ibrutinib resistance in mantle cell lymphoma (MCL) and showed that a small molecule can overcome that resistance in vitro and in vivo.
The team found that ibrutinib-resistant MCL cells rely on oxidative phosphorylation (OXPHOS) and glutaminolysis to survive.
Targeting the OXPHOS pathway with a small molecule, IACS-010759, inhibited the proliferation of ibrutinib-resistant cells in vitro.
IACS-010759 also decreased tumor volume and improved survival in mouse models of ibrutinib-resistant MCL and double-hit B-cell lymphoma.
Now, IACS-10759 is being tested in phase 1 trials of lymphoma and solid tumors (NCT03291938) as well as acute myeloid leukemia (NCT02882321).
Liang Zhang, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues conducted the preclinical research and described their findings in Science Translational Medicine.
The investigators sequenced samples from MCL patients with ibrutinib-sensitive and -resistant disease and found that “glutamine-fueled OXPHOS appears to be a prominent energy metabolism pathway in ibrutinib-resistant MCL cells.”
This finding prompted the team to test IACS-010759, an inhibitor of ETC complex I, in ibrutinib-resistant MCL. They theorized that the inhibitor would be effective because, during OXPHOS, electrons are transferred from electron donors to acceptors through the ETC in redox reactions that release energy to form ATP, and OXPHOS generates ATP to meet requirements for cell growth.
In experiments, IACS-010759 inhibited the proliferation of two ibrutinib-resistant MCL cell lines, Z-138 and Maver-1, in a dose-dependent manner.
The investigators also tested IACS-010759 in two mouse models of ibrutinib-resistant MCL. In both models, mice treated with IACS-010759 had a significant reduction in tumor volume, compared with controls. In one model, IACS-010759 extended survival by a median of 11 days.
Finally, the team tested IACS-010759 in a model of ibrutinib-resistant, double-hit (MYC and BCL-2) B-cell lymphoma with central nervous system involvement. Again, IACS-010759 significantly inhibited tumor growth. Compared to ibrutinib and vehicle control, IACS-010759 provided a median survival benefit of more than 20 days.
There were no toxicities associated with IACS-010759 treatment, according to the investigators.
This research was supported by the MD Anderson B Cell Lymphoma Moon Shot Project, Gary Rogers Foundation, Kinder Foundation, Cullen Foundation, Cancer Prevention Research Institute of Texas, and the National Institutes of Health. Most investigators reported having no competing interests, but two reported a patent (WO/2015/130790).
SOURCE: Zhang L et al. Sci Transl Med. 2019 May 8. doi: 10.1126/scitranslmed.aau1167.
Investigators have identified a mechanism of ibrutinib resistance in mantle cell lymphoma (MCL) and showed that a small molecule can overcome that resistance in vitro and in vivo.
The team found that ibrutinib-resistant MCL cells rely on oxidative phosphorylation (OXPHOS) and glutaminolysis to survive.
Targeting the OXPHOS pathway with a small molecule, IACS-010759, inhibited the proliferation of ibrutinib-resistant cells in vitro.
IACS-010759 also decreased tumor volume and improved survival in mouse models of ibrutinib-resistant MCL and double-hit B-cell lymphoma.
Now, IACS-10759 is being tested in phase 1 trials of lymphoma and solid tumors (NCT03291938) as well as acute myeloid leukemia (NCT02882321).
Liang Zhang, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues conducted the preclinical research and described their findings in Science Translational Medicine.
The investigators sequenced samples from MCL patients with ibrutinib-sensitive and -resistant disease and found that “glutamine-fueled OXPHOS appears to be a prominent energy metabolism pathway in ibrutinib-resistant MCL cells.”
This finding prompted the team to test IACS-010759, an inhibitor of ETC complex I, in ibrutinib-resistant MCL. They theorized that the inhibitor would be effective because, during OXPHOS, electrons are transferred from electron donors to acceptors through the ETC in redox reactions that release energy to form ATP, and OXPHOS generates ATP to meet requirements for cell growth.
In experiments, IACS-010759 inhibited the proliferation of two ibrutinib-resistant MCL cell lines, Z-138 and Maver-1, in a dose-dependent manner.
The investigators also tested IACS-010759 in two mouse models of ibrutinib-resistant MCL. In both models, mice treated with IACS-010759 had a significant reduction in tumor volume, compared with controls. In one model, IACS-010759 extended survival by a median of 11 days.
Finally, the team tested IACS-010759 in a model of ibrutinib-resistant, double-hit (MYC and BCL-2) B-cell lymphoma with central nervous system involvement. Again, IACS-010759 significantly inhibited tumor growth. Compared to ibrutinib and vehicle control, IACS-010759 provided a median survival benefit of more than 20 days.
There were no toxicities associated with IACS-010759 treatment, according to the investigators.
This research was supported by the MD Anderson B Cell Lymphoma Moon Shot Project, Gary Rogers Foundation, Kinder Foundation, Cullen Foundation, Cancer Prevention Research Institute of Texas, and the National Institutes of Health. Most investigators reported having no competing interests, but two reported a patent (WO/2015/130790).
SOURCE: Zhang L et al. Sci Transl Med. 2019 May 8. doi: 10.1126/scitranslmed.aau1167.
Investigators have identified a mechanism of ibrutinib resistance in mantle cell lymphoma (MCL) and showed that a small molecule can overcome that resistance in vitro and in vivo.
The team found that ibrutinib-resistant MCL cells rely on oxidative phosphorylation (OXPHOS) and glutaminolysis to survive.
Targeting the OXPHOS pathway with a small molecule, IACS-010759, inhibited the proliferation of ibrutinib-resistant cells in vitro.
IACS-010759 also decreased tumor volume and improved survival in mouse models of ibrutinib-resistant MCL and double-hit B-cell lymphoma.
Now, IACS-10759 is being tested in phase 1 trials of lymphoma and solid tumors (NCT03291938) as well as acute myeloid leukemia (NCT02882321).
Liang Zhang, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues conducted the preclinical research and described their findings in Science Translational Medicine.
The investigators sequenced samples from MCL patients with ibrutinib-sensitive and -resistant disease and found that “glutamine-fueled OXPHOS appears to be a prominent energy metabolism pathway in ibrutinib-resistant MCL cells.”
This finding prompted the team to test IACS-010759, an inhibitor of ETC complex I, in ibrutinib-resistant MCL. They theorized that the inhibitor would be effective because, during OXPHOS, electrons are transferred from electron donors to acceptors through the ETC in redox reactions that release energy to form ATP, and OXPHOS generates ATP to meet requirements for cell growth.
In experiments, IACS-010759 inhibited the proliferation of two ibrutinib-resistant MCL cell lines, Z-138 and Maver-1, in a dose-dependent manner.
The investigators also tested IACS-010759 in two mouse models of ibrutinib-resistant MCL. In both models, mice treated with IACS-010759 had a significant reduction in tumor volume, compared with controls. In one model, IACS-010759 extended survival by a median of 11 days.
Finally, the team tested IACS-010759 in a model of ibrutinib-resistant, double-hit (MYC and BCL-2) B-cell lymphoma with central nervous system involvement. Again, IACS-010759 significantly inhibited tumor growth. Compared to ibrutinib and vehicle control, IACS-010759 provided a median survival benefit of more than 20 days.
There were no toxicities associated with IACS-010759 treatment, according to the investigators.
This research was supported by the MD Anderson B Cell Lymphoma Moon Shot Project, Gary Rogers Foundation, Kinder Foundation, Cullen Foundation, Cancer Prevention Research Institute of Texas, and the National Institutes of Health. Most investigators reported having no competing interests, but two reported a patent (WO/2015/130790).
SOURCE: Zhang L et al. Sci Transl Med. 2019 May 8. doi: 10.1126/scitranslmed.aau1167.
FROM SCIENCE TRANSLATIONAL MEDICINE
FDA opts not to ban textured breast implants
The Food and Drug Administration decided to continue to allow U.S. sales of textured breast implants, which have been identified as the cause of a rare but significant cancer, breast implant–associated anaplastic large cell lymphoma.
A statement the agency released on May 2 said “The FDA does not believe that, on the basis of available data and information, the device [textured implants] meets the banning standard set forth in the Federal Food and Drug Cosmetic Act.” roughly half of them in the United States.
In coming to this decision, following 2 days of public testimony and discussions by an advisory committee in late March, the FDA is bucking the path taken by regulatory bodies of the European Union as well as several other counties. The EU acted in December 2018 to produce the equivalent of a ban on sales of textured breast implants marketed by Allergan. Then in April 2019, the French drug and device regulatory agency expanded this ban to textured breast implants sold by five other companies.
During the FDA advisory committee meeting in March, one of the world’s experts on BIA-ALCL, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, said that of about 500 case reports received by the FDA, not one had involved a confirmed and “pure” episode of BIA-ALCL linked with a smooth breast implant. A team of experts recently reached the same conclusion when reviewing the reported worldwide incidence of BIA-ALCL in a published review (Plast Reconstr Surg. 2019 March;143[3S]:30S-40S).
Despite these reports, the FDA said in its new statement that “While the majority of women who develop BIA-ALCL have had textured implants, there are known cases in women with smooth-surface breast implants, and many reports do not include the surface texture of the implant at the time of diagnosis.” The agency added that it is “focused on strengthening the evidence generated to help inform future regulatory action.” During the March advisory committee meeting, some members of the panel spoke against a marketing ban on textured implants for reasons such as the modest number of reported cases and because of the importance of having a textured implant option available.
The FDA took several other notable steps in its May 2 statement:
The agency formally acknowledged that many breast implant recipients have reported experiencing adverse effects that include chronic fatigue, cognitive issues, and joint and muscle pain. “While the FDA doesn’t have definitive evidence demonstrating breast implants cause these symptoms, the current evidence supports that some women experience systemic symptoms that may resolve when their breast implants are removed.” The agency also cited the term that patients have coined for these symptoms: Breast Implant Illness.
The FDA made a commitment to “take steps to improve the information available to women and health care professionals about the risks of breast implants,” including the risk for BIA-ALCL, the increased risk for this cancer with textured implants, and the risk for systemic symptoms. The agency said it would work with stakeholders on possible changes to breast implant labeling, including a possible boxed warning, and a patient-decision checklist.
The FDA announced a change in how manufacturers will file medical device reports for breast implants. The agency will no longer allow these filings to be “summary” reports and will instead require manufacturers to file full individual medical device reports for each case that will be publicly available, with the intent to make reporting more transparent and complete.
Finally, the FDA announced that it would partner with two U.S. breast implant registries, the PROFILE registry of BIA-ALCL cases, and the National Breast Implant Registry, both run by the Plastic Surgery Foundation.
The FDA did not address in its statement other issues that came up during the March advisory committee hearings, including a panel recommendation to change follow-up imaging from MRI to ultrasound for monitoring women with implants for rupture, and the extensive, off-label use of surgical mesh during breast implant surgery.
The Food and Drug Administration decided to continue to allow U.S. sales of textured breast implants, which have been identified as the cause of a rare but significant cancer, breast implant–associated anaplastic large cell lymphoma.
A statement the agency released on May 2 said “The FDA does not believe that, on the basis of available data and information, the device [textured implants] meets the banning standard set forth in the Federal Food and Drug Cosmetic Act.” roughly half of them in the United States.
In coming to this decision, following 2 days of public testimony and discussions by an advisory committee in late March, the FDA is bucking the path taken by regulatory bodies of the European Union as well as several other counties. The EU acted in December 2018 to produce the equivalent of a ban on sales of textured breast implants marketed by Allergan. Then in April 2019, the French drug and device regulatory agency expanded this ban to textured breast implants sold by five other companies.
During the FDA advisory committee meeting in March, one of the world’s experts on BIA-ALCL, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, said that of about 500 case reports received by the FDA, not one had involved a confirmed and “pure” episode of BIA-ALCL linked with a smooth breast implant. A team of experts recently reached the same conclusion when reviewing the reported worldwide incidence of BIA-ALCL in a published review (Plast Reconstr Surg. 2019 March;143[3S]:30S-40S).
Despite these reports, the FDA said in its new statement that “While the majority of women who develop BIA-ALCL have had textured implants, there are known cases in women with smooth-surface breast implants, and many reports do not include the surface texture of the implant at the time of diagnosis.” The agency added that it is “focused on strengthening the evidence generated to help inform future regulatory action.” During the March advisory committee meeting, some members of the panel spoke against a marketing ban on textured implants for reasons such as the modest number of reported cases and because of the importance of having a textured implant option available.
The FDA took several other notable steps in its May 2 statement:
The agency formally acknowledged that many breast implant recipients have reported experiencing adverse effects that include chronic fatigue, cognitive issues, and joint and muscle pain. “While the FDA doesn’t have definitive evidence demonstrating breast implants cause these symptoms, the current evidence supports that some women experience systemic symptoms that may resolve when their breast implants are removed.” The agency also cited the term that patients have coined for these symptoms: Breast Implant Illness.
The FDA made a commitment to “take steps to improve the information available to women and health care professionals about the risks of breast implants,” including the risk for BIA-ALCL, the increased risk for this cancer with textured implants, and the risk for systemic symptoms. The agency said it would work with stakeholders on possible changes to breast implant labeling, including a possible boxed warning, and a patient-decision checklist.
The FDA announced a change in how manufacturers will file medical device reports for breast implants. The agency will no longer allow these filings to be “summary” reports and will instead require manufacturers to file full individual medical device reports for each case that will be publicly available, with the intent to make reporting more transparent and complete.
Finally, the FDA announced that it would partner with two U.S. breast implant registries, the PROFILE registry of BIA-ALCL cases, and the National Breast Implant Registry, both run by the Plastic Surgery Foundation.
The FDA did not address in its statement other issues that came up during the March advisory committee hearings, including a panel recommendation to change follow-up imaging from MRI to ultrasound for monitoring women with implants for rupture, and the extensive, off-label use of surgical mesh during breast implant surgery.
The Food and Drug Administration decided to continue to allow U.S. sales of textured breast implants, which have been identified as the cause of a rare but significant cancer, breast implant–associated anaplastic large cell lymphoma.
A statement the agency released on May 2 said “The FDA does not believe that, on the basis of available data and information, the device [textured implants] meets the banning standard set forth in the Federal Food and Drug Cosmetic Act.” roughly half of them in the United States.
In coming to this decision, following 2 days of public testimony and discussions by an advisory committee in late March, the FDA is bucking the path taken by regulatory bodies of the European Union as well as several other counties. The EU acted in December 2018 to produce the equivalent of a ban on sales of textured breast implants marketed by Allergan. Then in April 2019, the French drug and device regulatory agency expanded this ban to textured breast implants sold by five other companies.
During the FDA advisory committee meeting in March, one of the world’s experts on BIA-ALCL, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, said that of about 500 case reports received by the FDA, not one had involved a confirmed and “pure” episode of BIA-ALCL linked with a smooth breast implant. A team of experts recently reached the same conclusion when reviewing the reported worldwide incidence of BIA-ALCL in a published review (Plast Reconstr Surg. 2019 March;143[3S]:30S-40S).
Despite these reports, the FDA said in its new statement that “While the majority of women who develop BIA-ALCL have had textured implants, there are known cases in women with smooth-surface breast implants, and many reports do not include the surface texture of the implant at the time of diagnosis.” The agency added that it is “focused on strengthening the evidence generated to help inform future regulatory action.” During the March advisory committee meeting, some members of the panel spoke against a marketing ban on textured implants for reasons such as the modest number of reported cases and because of the importance of having a textured implant option available.
The FDA took several other notable steps in its May 2 statement:
The agency formally acknowledged that many breast implant recipients have reported experiencing adverse effects that include chronic fatigue, cognitive issues, and joint and muscle pain. “While the FDA doesn’t have definitive evidence demonstrating breast implants cause these symptoms, the current evidence supports that some women experience systemic symptoms that may resolve when their breast implants are removed.” The agency also cited the term that patients have coined for these symptoms: Breast Implant Illness.
The FDA made a commitment to “take steps to improve the information available to women and health care professionals about the risks of breast implants,” including the risk for BIA-ALCL, the increased risk for this cancer with textured implants, and the risk for systemic symptoms. The agency said it would work with stakeholders on possible changes to breast implant labeling, including a possible boxed warning, and a patient-decision checklist.
The FDA announced a change in how manufacturers will file medical device reports for breast implants. The agency will no longer allow these filings to be “summary” reports and will instead require manufacturers to file full individual medical device reports for each case that will be publicly available, with the intent to make reporting more transparent and complete.
Finally, the FDA announced that it would partner with two U.S. breast implant registries, the PROFILE registry of BIA-ALCL cases, and the National Breast Implant Registry, both run by the Plastic Surgery Foundation.
The FDA did not address in its statement other issues that came up during the March advisory committee hearings, including a panel recommendation to change follow-up imaging from MRI to ultrasound for monitoring women with implants for rupture, and the extensive, off-label use of surgical mesh during breast implant surgery.
CAR T-cell therapy bb2121 performs well in phase 1 trial of refractory multiple myeloma
Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.
The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.
The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.
The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.
After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.
All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.
The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.
SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.
Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.
The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.
The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.
The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.
After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.
All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.
The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.
SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.
Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.
The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.
The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.
The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.
After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.
All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.
The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.
SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
High-dose MTX-based chemo is well tolerated in older PCNSL patients
GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.
For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.
Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.
Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.
“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”
This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.
The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.
The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.
The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.
The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.
Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).
Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.
A closer look at the data revealed some patterns, Dr. Poynton said.
“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.
Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.
Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.
Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”
He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.
“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”
Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.
GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.
For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.
Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.
Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.
“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”
This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.
The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.
The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.
The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.
The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.
Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).
Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.
A closer look at the data revealed some patterns, Dr. Poynton said.
“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.
Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.
Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.
Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”
He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.
“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”
Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.
GLASGOW – Most older patients with primary central nervous system lymphoma (PCNSL) can tolerate high-dose methotrexate-based chemotherapy and achieve similar outcomes as younger and fitter patients, according to a retrospective analysis of 244 patients in the United Kingdom.
For older patients – at least 65 years old – who received methotrexate-based regimens, treatment-related mortality was 6.8%, which is comparable with rates seen in trials involving younger patients, reported lead author Edward Poynton, MD, of University College Hospital in London.
Specifically, Dr. Poynton cited the phase 2 IELSG32 trial, which had a treatment-related mortality rate of 6% among patients up to age 70 years. These patients were treated with the established protocol for younger patients: chemotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix) followed by autologous stem cell transplant or whole-brain radiotherapy.
Introducing Dr. Poynton’s presentation at the annual meeting of the British Society for Haematology, Simon Rule, MD, of the University of Plymouth (England), added historical context to the new findings.
“When I started in hematology ... [PCNSL] was a universally fatal disease, pretty much,” Dr. Rule said. “And then we had methotrexate, and it worked occasionally. And then we had a randomized trial, which was randomization of methotrexate plus or minus high-dose cytarabine, showing benefit.”
This combination became the benchmark against which subsequent randomized trials were measured; however, such high-intensity regimens have raised concerns about safety and efficacy in older patients, Dr. Rule said, noting that the present study serves to inform clinicians about real-world outcomes in this population.
The retrospective analysis reviewed 244 patients who were aged at least 65 years when histologically diagnosed with PCNSL at 14 U.K. tertiary centers between 2012 and 2017. All patients received first-line care of any kind, ranging from best supportive care to clinical trial therapy. Patients were grouped into three treatment cohorts divided by level of frailty. Analysis showed that these divisions correlated with age, renal function, Eastern Cooperative Oncology Group performance status, and treatment intensity.
The frail group received palliative treatment consisting of whole-brain radiotherapy, an oral alkylator, or best supportive care. The less-fit group received methotrexate in combination with rituximab, an oral alkylator, or both. The fit group was most intensively treated, receiving high-dose methotrexate and cytarabine – with or without rituximab – or MATRix.
The primary objective was overall response rate, while the secondary objectives were median overall survival and progression-free survival.
The analysis showed that 79% of patients (n = 193) received methotrexate-based therapy of some kind, with 61% receiving three or more cycles of therapy and 30% requiring dose reductions. The overall response rate was 63%.
Dr. Poynton noted that about two-thirds of patients who achieved a partial response in early assessment went on to achieve a complete response. Patients in the fit group more often responded than those who were less fit (87% vs. 65%; P = .01) and more often received consolidation therapy (42% vs. 23%; P = .01).
Fitness level was also associated with median overall survival, which was longest in the fit group at 42 months. The other two groups had dramatically shorter survival times: 8 months in the less-fit group and just 2 months in the frail group.
A closer look at the data revealed some patterns, Dr. Poynton said.
“What we see is that age at diagnosis is significantly correlated with progression-free survival but not with overall survival,” he said, noting that, in contrast, performance status was associated with both survival measures.
Methotrexate dose also impacted both survival measures. Patients who received 75% or more of their induction dose over the course of treatment had better median overall survival and progression-free survival than those who received less than 75%. Similarly, consolidation therapy improved both survival measures.
Patients aged older than 70 years who received intensive chemotherapy had a treatment-related mortality rate of 4.8%, which is lower than the overall treatment-related mortality, Dr. Poynton reported.
Considering the correlation between methotrexate dose and survival, Dr. Poynton suggested that “dose reductions should be carefully considered.”
He also noted that patients in the fit cohort who received intensive chemotherapy had comparable outcomes with younger patients in prospective trials, and yet 44% of patients older than 65 years in the real world who received high-dose methotrexate with cytarabine would have been ineligible for the IELSG32 trial.
“We’ve been able to identify this cohort of patients retrospectively,” Dr. Poynton said. “They definitely exist, and I think we need to work harder at how are going to identify these patients prospectively in the future, so we know which of our patients who are older can benefit from intensive chemotherapy and which patients won’t.”
Dr. Poynton reported having no relevant financial disclosures. His coinvestigators reported relationships with AbbVie, Merck, Takeda, Jazz Pharmaceuticals, and others.
REPORTING FROM BSH 2019
Monitoring, early intervention key to CAR T safety
GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.
As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.
“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”
Monitoring
Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.
“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”
Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.
“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”
At MD Anderson, these earlier interventions have decreased severity of adverse events.
“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.
Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.
“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”
Grading toxicity
In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.
“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”
She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.
To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.
“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.
With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.
“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”
Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.
Choosing therapy
When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.
“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”
According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.
“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.
Dr. Nastoupil concluded her presentation with an overview and look to the future.
“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”
Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”
Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.
GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.
As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.
“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”
Monitoring
Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.
“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”
Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.
“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”
At MD Anderson, these earlier interventions have decreased severity of adverse events.
“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.
Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.
“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”
Grading toxicity
In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.
“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”
She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.
To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.
“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.
With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.
“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”
Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.
Choosing therapy
When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.
“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”
According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.
“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.
Dr. Nastoupil concluded her presentation with an overview and look to the future.
“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”
Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”
Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.
GLASGOW – Constant patient monitoring and early intervention with tocilizumab and steroids are essential to the safe delivery of chimeric antigen receptor (CAR) T-cell therapy in patients with non-Hodgkin lymphoma (NHL), according to a leading expert.
As a clinical researcher at MD Anderson Cancer Center in Houston, Loretta Nastoupil, MD has played an active role in the evolution of CAR T-cell therapy, from early trials to ongoing development of treatment protocols. During a presentation at the annual meeting of the British Society for Haematology, Dr. Nastoupil discussed leading topics in CAR T-cell therapy, with an emphasis on safe delivery.
“[Toxicity] is something we don’t talk about as much as we should, partly because this therapy works and it’s really exciting,” Dr. Nastoupil said. “But the toxicity is not something that I minimize, and it’s very challenging. It’s led us to restructure our inpatient services. It’s led to a lot of sleepless nights. These patients can do very, very well, or they can do very, very poorly in terms of toxicity and I think the most important strategy is recognition and early intervention.”
Monitoring
Early recognition depends on close monitoring, Dr. Nastoupil said, which is carried out by highly trained nursing staff who follow therapy-specific decision algorithms.
“We have nurses that are on the front line,” Dr. Nastoupil said. “They’re the most important group. We have staff that round on [patients] daily, but the nurses are there 24 hours a day. We have a flow sheet where they grade cytokine release syndrome and neurotoxicity every 8 hours, or if there is an acute change in symptoms or toxicity, they’ll do it in real time.”
Dr. Nastoupil said that if these toxicities are detected, intervention is occurring sooner than it did with some of the first patients to receive CAR-T cell therapy.
“Initially there was a lot of fear surrounding anything that would abort the CAR-T cell therapy,” Dr. Nastoupil said. “There was concern that if you were trying to mitigate some of the toxicity you might have a negative impact on efficacy ... [W]ith the first iteration of studies, generally we were waiting until grade 3 or higher cytokine release syndrome before initiating either tocilizumab and/or steroids. As the studies evolved, it started to move into grade 2 toxicity that we started using therapy, mostly because we started to see that those patients were still responding.”
At MD Anderson, these earlier interventions have decreased severity of adverse events.
“It’s rare nowadays to have grade 3 or 4 cytokine release syndrome because we are generally introducing abortive therapy at grade 2,” Dr. Nastoupil said, citing increased use of steroids and tocilizumab.
Currently, no consensus exists for managing these events, partly because clinicians are still learning about best management practices.
“There will be a consensus on management,” Dr. Nastoupil said. “I think that’s needed. The problem is, it will probably evolve as we get more experience with managing these patients. I think there’s been a little hesitation to put something out on paper knowing that a year from now that might change.”
Grading toxicity
In contrast, Dr. Nastoupil said that a consensus has been reached for grading acute toxicity. Of note, fever is now considered an essential element of cytokine release syndrome.
“The first thing we see [with cytokine release syndrome] is fever, generally speaking,” Dr. Nastoupil said. “That will prompt a workup for infection because these patients are going to be neutropenic. And we initiate broad spectrum antimicrobials.”
She said that some patients treated with CAR T-cell therapy have had disseminated fungal infections, so clinicians need to be on the lookout for septic shock.
To assess neurotoxicity, the team at MD Anderson uses an objective scoring system, called “CARTOX.” This helps maintain consistency when facing broadly different neurological presentations.
“There’s such a wide ranging spectrum of patients that are undergoing neurotoxicity you can’t expect someone, even myself, to be consistent when you are trying to tease out how serious it is,” Dr. Nastoupil said.
With CARTOX, nurses can easily score patients and call clinicians with results. Still, this doesn’t eliminate difficulties inherent to managing neurotoxicity, particularly when it is severe.
“I’d say one of the areas that is still very challenging is when [patients with neurotoxicity] are no longer responding,” Dr. Nastoupil said. “You have to be very mindful of seizure activity. We’ve had a couple of patients with status [epilepticus]. You don’t see seizure activity physically, but when you do an EEG, you pick it up.”
Dr. Nastoupil added that most centers are now giving patients prophylactic levetiracetam (Keppra) to lower seizure risk.
Choosing therapy
When selecting between the two therapies currently approved by the Food and Drug Administration – tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) – based on safety, Dr. Nastoupil said that rates of cytokine release syndrome appear similar, but neurotoxicity rates may differ.
“Cytokine release syndrome in my opinion is probably more similar than different in terms of grade 3 or higher because tocilizumab and steroids work quite well in aborting those toxicities,” Dr. Nastoupil said. “But neurotoxicity still sticks out in my mind as the most striking difference, where with axicabtagene you see more grade 3 or higher neurotoxicity, though very, very few deaths as a result of this. But it’s very challenging in terms of management.”
According to Dr. Nastoupil, comparisons between CAR T-cell therapies have been complicated by differences in clinical trial methodologies. However, she offered a general conclusion regarding efficacy.
“[W]hat I’ll tell you, at the end of the day, is [that existing CAR T-cell therapies] all seem to sort of settle out around 30%-40% in terms of durable responses,” Dr. Nastoupil said.
Dr. Nastoupil concluded her presentation with an overview and look to the future.
“I do think [CAR T-cell therapy] is transformative, particularly for our chemo refractory patients,” she said. “There is nothing else like it. The problem right now is that it is only durable in 40% of patients. So can we be better at selecting out patients that are more likely to respond? Does introducing this in earlier lines of therapy increase that fraction of patients that are potentially cured?”
Considering these questions, she said: “We need more patients. We need more data. We need longer follow-up to understand the nuances of this therapy.”
Dr. Nastoupil previously reported financial relationships with Celgene, Genentech, Gilead, Merck, Novartis, Spectrum, and TG Therapeutics.
EXPERT ANALYSIS FROM BSH 2019
Quality of life decrement with salvage ASCT is short-lived
For patients with multiple myeloma in relapse after an autologous stem cell transplant (ASCT), salvage ASCT is associated with reduced quality of life and greater pain in the near term, compared with nontransplantation consolidation (NTC) therapy, a secondary analysis from the United Kingdom’s Myeloma X trial suggested.
But global health status scores for salvage ASCT (sASCT) lagged only in the first 100 days after randomization, whereas pain scores were worse with salvage transplantation in the first 2 years but slightly better thereafter, reported Sam H. Ahmedzai, MBChB, from the University of Sheffield, England, and his colleagues.
“The small and diminishing differences in global health status and side effects of treatment need to be considered alongside the results of Myeloma X, which showed a significant benefit of sASCT on [overall survival]. The benefits of sASCT should be considered alongside the relatively short-term negative effects on [quality of life] and pain when making patient treatment decisions and further support the use of sASCT,” they wrote in the Journal of Clinical Oncology.
The BSBMT/UKMF Myeloma X trial was a multicenter, randomized, phase 3 trial comparing sASCT with weekly oral cyclophosphamide in patients with multiple myeloma who had relapsed after a prior ASCT. In the final overall survival analysis, median overall survival was superior for the sASCT, at 67 months vs. 52 months for nontransplantation consolidation (P = .022; hazard ratio, 0.56; P = .0169).
In the current study, the investigators reported on secondary patient-reported pain and quality of life outcomes assessed using the validated European Organization for Research and Treatment of Cancer Questionnaire (QLQ-C30) and its myeloma-specific module, QLQ-MY20; the Brief Pain Inventory (Short Form), and the Leeds Assessment of Neuropathic Symptoms and Signs (Self-Assessment) scale.
Of the 297 patients enrolled, 288 had consented to the quality of life portion of the study, and of this group, 171 (88 assigned to sASCT and 83 assigned to NTC) were included.
After a median follow-up of 52 months, the QLQ-C30 global health status scores were 9.2 points higher (indicating better) for patients in the nontransplantation group (P = .0496) at 100 days after transplantation, but there were no significant differences between the groups for this measure at any later time point.
“This deterioration in global health status for patients receiving sASCT, compared with NTC, dissipated to a trivial difference at 6 months and a smaller trivial difference at 1 year,” Dr. Ahmedzai and his colleagues wrote.
At 2 years, the pendulum had swung to favor sASCT, but also by a “trivial” amount.
The side effects of treatment subscale was slightly higher (worse) with sASCT at 100 days and 6 months after treatment, but this difference dwindled thereafter.
Pain interference scores adjusted for baseline score and baseline neuropathic pain level were not significantly different 100 days after randomization, but there were significant differences at both 6 months and up to 2 years. At all the time points considered, pain interference scores were approximately 1 point lower in the NTC group, which the authors noted is a clinically relevant difference.
Patients who had undergone sASCT and reported below-median scores on a side-effect subscale had significantly longer time to progression, compared with patients who received NTC (HR, 0.24; P = .003), a difference that held up on multivariable regression analysis (HR, 0.20; P = .0499).
Pain scores were not significantly predictive of either time to progression or overall survival, however.
The study was supported by Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK. Dr. Ahmedzai reported honoraria, consulting, research funding, and travel fees from various companies, not including the study sponsors.
SOURCE: Ahmedzai SH et al. J Clin Oncol. 2019 Apr 10. doi: 10.1200/JCO.18.01006.
For patients with multiple myeloma in relapse after an autologous stem cell transplant (ASCT), salvage ASCT is associated with reduced quality of life and greater pain in the near term, compared with nontransplantation consolidation (NTC) therapy, a secondary analysis from the United Kingdom’s Myeloma X trial suggested.
But global health status scores for salvage ASCT (sASCT) lagged only in the first 100 days after randomization, whereas pain scores were worse with salvage transplantation in the first 2 years but slightly better thereafter, reported Sam H. Ahmedzai, MBChB, from the University of Sheffield, England, and his colleagues.
“The small and diminishing differences in global health status and side effects of treatment need to be considered alongside the results of Myeloma X, which showed a significant benefit of sASCT on [overall survival]. The benefits of sASCT should be considered alongside the relatively short-term negative effects on [quality of life] and pain when making patient treatment decisions and further support the use of sASCT,” they wrote in the Journal of Clinical Oncology.
The BSBMT/UKMF Myeloma X trial was a multicenter, randomized, phase 3 trial comparing sASCT with weekly oral cyclophosphamide in patients with multiple myeloma who had relapsed after a prior ASCT. In the final overall survival analysis, median overall survival was superior for the sASCT, at 67 months vs. 52 months for nontransplantation consolidation (P = .022; hazard ratio, 0.56; P = .0169).
In the current study, the investigators reported on secondary patient-reported pain and quality of life outcomes assessed using the validated European Organization for Research and Treatment of Cancer Questionnaire (QLQ-C30) and its myeloma-specific module, QLQ-MY20; the Brief Pain Inventory (Short Form), and the Leeds Assessment of Neuropathic Symptoms and Signs (Self-Assessment) scale.
Of the 297 patients enrolled, 288 had consented to the quality of life portion of the study, and of this group, 171 (88 assigned to sASCT and 83 assigned to NTC) were included.
After a median follow-up of 52 months, the QLQ-C30 global health status scores were 9.2 points higher (indicating better) for patients in the nontransplantation group (P = .0496) at 100 days after transplantation, but there were no significant differences between the groups for this measure at any later time point.
“This deterioration in global health status for patients receiving sASCT, compared with NTC, dissipated to a trivial difference at 6 months and a smaller trivial difference at 1 year,” Dr. Ahmedzai and his colleagues wrote.
At 2 years, the pendulum had swung to favor sASCT, but also by a “trivial” amount.
The side effects of treatment subscale was slightly higher (worse) with sASCT at 100 days and 6 months after treatment, but this difference dwindled thereafter.
Pain interference scores adjusted for baseline score and baseline neuropathic pain level were not significantly different 100 days after randomization, but there were significant differences at both 6 months and up to 2 years. At all the time points considered, pain interference scores were approximately 1 point lower in the NTC group, which the authors noted is a clinically relevant difference.
Patients who had undergone sASCT and reported below-median scores on a side-effect subscale had significantly longer time to progression, compared with patients who received NTC (HR, 0.24; P = .003), a difference that held up on multivariable regression analysis (HR, 0.20; P = .0499).
Pain scores were not significantly predictive of either time to progression or overall survival, however.
The study was supported by Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK. Dr. Ahmedzai reported honoraria, consulting, research funding, and travel fees from various companies, not including the study sponsors.
SOURCE: Ahmedzai SH et al. J Clin Oncol. 2019 Apr 10. doi: 10.1200/JCO.18.01006.
For patients with multiple myeloma in relapse after an autologous stem cell transplant (ASCT), salvage ASCT is associated with reduced quality of life and greater pain in the near term, compared with nontransplantation consolidation (NTC) therapy, a secondary analysis from the United Kingdom’s Myeloma X trial suggested.
But global health status scores for salvage ASCT (sASCT) lagged only in the first 100 days after randomization, whereas pain scores were worse with salvage transplantation in the first 2 years but slightly better thereafter, reported Sam H. Ahmedzai, MBChB, from the University of Sheffield, England, and his colleagues.
“The small and diminishing differences in global health status and side effects of treatment need to be considered alongside the results of Myeloma X, which showed a significant benefit of sASCT on [overall survival]. The benefits of sASCT should be considered alongside the relatively short-term negative effects on [quality of life] and pain when making patient treatment decisions and further support the use of sASCT,” they wrote in the Journal of Clinical Oncology.
The BSBMT/UKMF Myeloma X trial was a multicenter, randomized, phase 3 trial comparing sASCT with weekly oral cyclophosphamide in patients with multiple myeloma who had relapsed after a prior ASCT. In the final overall survival analysis, median overall survival was superior for the sASCT, at 67 months vs. 52 months for nontransplantation consolidation (P = .022; hazard ratio, 0.56; P = .0169).
In the current study, the investigators reported on secondary patient-reported pain and quality of life outcomes assessed using the validated European Organization for Research and Treatment of Cancer Questionnaire (QLQ-C30) and its myeloma-specific module, QLQ-MY20; the Brief Pain Inventory (Short Form), and the Leeds Assessment of Neuropathic Symptoms and Signs (Self-Assessment) scale.
Of the 297 patients enrolled, 288 had consented to the quality of life portion of the study, and of this group, 171 (88 assigned to sASCT and 83 assigned to NTC) were included.
After a median follow-up of 52 months, the QLQ-C30 global health status scores were 9.2 points higher (indicating better) for patients in the nontransplantation group (P = .0496) at 100 days after transplantation, but there were no significant differences between the groups for this measure at any later time point.
“This deterioration in global health status for patients receiving sASCT, compared with NTC, dissipated to a trivial difference at 6 months and a smaller trivial difference at 1 year,” Dr. Ahmedzai and his colleagues wrote.
At 2 years, the pendulum had swung to favor sASCT, but also by a “trivial” amount.
The side effects of treatment subscale was slightly higher (worse) with sASCT at 100 days and 6 months after treatment, but this difference dwindled thereafter.
Pain interference scores adjusted for baseline score and baseline neuropathic pain level were not significantly different 100 days after randomization, but there were significant differences at both 6 months and up to 2 years. At all the time points considered, pain interference scores were approximately 1 point lower in the NTC group, which the authors noted is a clinically relevant difference.
Patients who had undergone sASCT and reported below-median scores on a side-effect subscale had significantly longer time to progression, compared with patients who received NTC (HR, 0.24; P = .003), a difference that held up on multivariable regression analysis (HR, 0.20; P = .0499).
Pain scores were not significantly predictive of either time to progression or overall survival, however.
The study was supported by Cancer Research UK, Janssen-Cilag, and Chugai Pharma UK. Dr. Ahmedzai reported honoraria, consulting, research funding, and travel fees from various companies, not including the study sponsors.
SOURCE: Ahmedzai SH et al. J Clin Oncol. 2019 Apr 10. doi: 10.1200/JCO.18.01006.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
RIT consolidation may be an option for unfit MCL patients
For older, less fit patients with mantle cell lymphoma (MCL) who may not be able to withstand the rigors of autologous stem cell transplants (ASCT), induction chemotherapy followed by radioimmunotherapy (RIT) consolidation with ibritumomab tiuxetan (Zevalin) was associated with good response rates and promising progression-free and overall survival rates, according to results of a phase 2 prospective study.
RIT consolidation improved the complete response rate following first-line therapy from 41% to 91%, reported Wojciech Jurczak, MD, PhD, from the department of hematology at the Uniwersytet Jagiellonski in Krakow, Poland, and colleagues.
In the patients who received RIT following first-line induction, median progression-free survival was 3.3 years, and median overall survival was 6.5 years.
“The achieved responses are durable. Although, several novel agents and targeted therapies alone or in combination are currently being studied and developed in both the upfront and relapsed settings, RIT constitutes a valid and underused option especially in the first-line setting,” they wrote in a study published in Leukemia & Lymphoma.
The investigators enrolled 46 patients with clinical stage III to IV MCL who were either ineligible for, or unwilling to undergo, ASCT. The cohort included 34 patients with newly diagnosed advanced MCL and 12 with chemo-sensitive MCL in first relapse.
Patients were assigned to induction with six cycles of chemotherapy, with or without rituximab. Patients then underwent consolidation with RIT if they had confirmed reductions of the maximal lymph node diameter below 3 cm, their longest spleen measurement was below 15 cm, and bone marrow infiltration was less than 20%.
The chemotherapy regimens included either CVP (cyclophosphamide, vincristine and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), FC (fludarabine and cyclophosphamide), or FCM (FC plus mitoxantrone). Additionally, 27 of the 46 patients received rituximab, which was not considered the standard of care in Poland when the study began in 2005 and was delivered based on availability.
Of the 34 patients who received first-line chemotherapy, 20 received FC or FCM (with or without rituximab), and 14 received CHOP or CVP (with or without rituximab). In this group, 14 patients (41%) had a complete response, and 20 (95%) had a partial response. Of the 12 patients treated after first relapse, two (17%) had a complete response and 10 (83%) had partial response after induction.
RIT consolidation was performed 3-5 weeks after the last chemotherapy cycle. Patients with cytopenias after chemotherapy could wait an additional 3 weeks, during which they would receive a bridging dose of rituximab at the standard 375 mg/m2 dose. The patients received two doses of rituximab 250 mg/m2 administered 7 days then 24 hours prior to intravenous injection of 90Y-labeled ibritumomab tiuxetan. The radiation doses delivered were 0.4 mCi/kg for patients with normal platelet counts and 0.3 mCi/kg for those with platelet counts from 100,000 to 150,000 cells/mm3. The maximum dose was 32.0 mCi.
The longest follow-up was out to slightly more than 8 years.
For the patients who received RIT after first-line induction, the complete response rate was 91%, and the partial response rate was 9%, compared with 41% complete response and 59% partial response after induction. In this group, the median progression-free survival was 3.3 years, and the median overall survival was 6.5 years.
For the patients who received RIT consolidation after first relapse and second chemotherapy regimen, the complete response rate was 75% and the partial response rate was 25%, compared with 17% and 83% at the end of second induction therapy. In this group, the median progression-free survival was 1.8 years (P less than .05, compared with patients treated after first-line responses), and the median overall survival was 2.2 years (P less than .05).
At 8 years of follow-up, 30% of patients who received RIT consolidation following first-line therapy were alive.
Adverse events included cytopenias in the majority of patients (77%), which were grade 1 or 2 in severity in 43% and grade 3 or 4 in 34%. Grade 3 or 4 thrombocytopenia and leukopenia occurred more frequently in patients treated with fludarabine-based regimens, and the thrombocytopenias in these patients lasted longer and required more platelet transfusions than those in CHOP- or CVP-treated patients. Two patients who underwent RIT following FCM induction died from prolonged thrombocytopenia, resulting in hemorrhagic strokes.
Among all patients, 22 patients developed infections following RIT consolidation. Five patients, all of whom had received fludarabine, required hospitalization for the treatment of the infections. There were no infection-related deaths, however.
Five patients developed the myelodysplastic syndrome, with a median onset time of 26 months. Of these patients, four had received fludarabine, and one had undergone a prior ASCT.
The trial was sponsored by Schering AG. Dr. Jurczak reported speakers bureau participation and research funding from multiple companies, not including Schering AG.
SOURCE: Jurczak W et al. Leuk Lymphoma. 2019 Apr 9. doi: 10.1080/10428194.2019.1602261.
For older, less fit patients with mantle cell lymphoma (MCL) who may not be able to withstand the rigors of autologous stem cell transplants (ASCT), induction chemotherapy followed by radioimmunotherapy (RIT) consolidation with ibritumomab tiuxetan (Zevalin) was associated with good response rates and promising progression-free and overall survival rates, according to results of a phase 2 prospective study.
RIT consolidation improved the complete response rate following first-line therapy from 41% to 91%, reported Wojciech Jurczak, MD, PhD, from the department of hematology at the Uniwersytet Jagiellonski in Krakow, Poland, and colleagues.
In the patients who received RIT following first-line induction, median progression-free survival was 3.3 years, and median overall survival was 6.5 years.
“The achieved responses are durable. Although, several novel agents and targeted therapies alone or in combination are currently being studied and developed in both the upfront and relapsed settings, RIT constitutes a valid and underused option especially in the first-line setting,” they wrote in a study published in Leukemia & Lymphoma.
The investigators enrolled 46 patients with clinical stage III to IV MCL who were either ineligible for, or unwilling to undergo, ASCT. The cohort included 34 patients with newly diagnosed advanced MCL and 12 with chemo-sensitive MCL in first relapse.
Patients were assigned to induction with six cycles of chemotherapy, with or without rituximab. Patients then underwent consolidation with RIT if they had confirmed reductions of the maximal lymph node diameter below 3 cm, their longest spleen measurement was below 15 cm, and bone marrow infiltration was less than 20%.
The chemotherapy regimens included either CVP (cyclophosphamide, vincristine and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), FC (fludarabine and cyclophosphamide), or FCM (FC plus mitoxantrone). Additionally, 27 of the 46 patients received rituximab, which was not considered the standard of care in Poland when the study began in 2005 and was delivered based on availability.
Of the 34 patients who received first-line chemotherapy, 20 received FC or FCM (with or without rituximab), and 14 received CHOP or CVP (with or without rituximab). In this group, 14 patients (41%) had a complete response, and 20 (95%) had a partial response. Of the 12 patients treated after first relapse, two (17%) had a complete response and 10 (83%) had partial response after induction.
RIT consolidation was performed 3-5 weeks after the last chemotherapy cycle. Patients with cytopenias after chemotherapy could wait an additional 3 weeks, during which they would receive a bridging dose of rituximab at the standard 375 mg/m2 dose. The patients received two doses of rituximab 250 mg/m2 administered 7 days then 24 hours prior to intravenous injection of 90Y-labeled ibritumomab tiuxetan. The radiation doses delivered were 0.4 mCi/kg for patients with normal platelet counts and 0.3 mCi/kg for those with platelet counts from 100,000 to 150,000 cells/mm3. The maximum dose was 32.0 mCi.
The longest follow-up was out to slightly more than 8 years.
For the patients who received RIT after first-line induction, the complete response rate was 91%, and the partial response rate was 9%, compared with 41% complete response and 59% partial response after induction. In this group, the median progression-free survival was 3.3 years, and the median overall survival was 6.5 years.
For the patients who received RIT consolidation after first relapse and second chemotherapy regimen, the complete response rate was 75% and the partial response rate was 25%, compared with 17% and 83% at the end of second induction therapy. In this group, the median progression-free survival was 1.8 years (P less than .05, compared with patients treated after first-line responses), and the median overall survival was 2.2 years (P less than .05).
At 8 years of follow-up, 30% of patients who received RIT consolidation following first-line therapy were alive.
Adverse events included cytopenias in the majority of patients (77%), which were grade 1 or 2 in severity in 43% and grade 3 or 4 in 34%. Grade 3 or 4 thrombocytopenia and leukopenia occurred more frequently in patients treated with fludarabine-based regimens, and the thrombocytopenias in these patients lasted longer and required more platelet transfusions than those in CHOP- or CVP-treated patients. Two patients who underwent RIT following FCM induction died from prolonged thrombocytopenia, resulting in hemorrhagic strokes.
Among all patients, 22 patients developed infections following RIT consolidation. Five patients, all of whom had received fludarabine, required hospitalization for the treatment of the infections. There were no infection-related deaths, however.
Five patients developed the myelodysplastic syndrome, with a median onset time of 26 months. Of these patients, four had received fludarabine, and one had undergone a prior ASCT.
The trial was sponsored by Schering AG. Dr. Jurczak reported speakers bureau participation and research funding from multiple companies, not including Schering AG.
SOURCE: Jurczak W et al. Leuk Lymphoma. 2019 Apr 9. doi: 10.1080/10428194.2019.1602261.
For older, less fit patients with mantle cell lymphoma (MCL) who may not be able to withstand the rigors of autologous stem cell transplants (ASCT), induction chemotherapy followed by radioimmunotherapy (RIT) consolidation with ibritumomab tiuxetan (Zevalin) was associated with good response rates and promising progression-free and overall survival rates, according to results of a phase 2 prospective study.
RIT consolidation improved the complete response rate following first-line therapy from 41% to 91%, reported Wojciech Jurczak, MD, PhD, from the department of hematology at the Uniwersytet Jagiellonski in Krakow, Poland, and colleagues.
In the patients who received RIT following first-line induction, median progression-free survival was 3.3 years, and median overall survival was 6.5 years.
“The achieved responses are durable. Although, several novel agents and targeted therapies alone or in combination are currently being studied and developed in both the upfront and relapsed settings, RIT constitutes a valid and underused option especially in the first-line setting,” they wrote in a study published in Leukemia & Lymphoma.
The investigators enrolled 46 patients with clinical stage III to IV MCL who were either ineligible for, or unwilling to undergo, ASCT. The cohort included 34 patients with newly diagnosed advanced MCL and 12 with chemo-sensitive MCL in first relapse.
Patients were assigned to induction with six cycles of chemotherapy, with or without rituximab. Patients then underwent consolidation with RIT if they had confirmed reductions of the maximal lymph node diameter below 3 cm, their longest spleen measurement was below 15 cm, and bone marrow infiltration was less than 20%.
The chemotherapy regimens included either CVP (cyclophosphamide, vincristine and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), FC (fludarabine and cyclophosphamide), or FCM (FC plus mitoxantrone). Additionally, 27 of the 46 patients received rituximab, which was not considered the standard of care in Poland when the study began in 2005 and was delivered based on availability.
Of the 34 patients who received first-line chemotherapy, 20 received FC or FCM (with or without rituximab), and 14 received CHOP or CVP (with or without rituximab). In this group, 14 patients (41%) had a complete response, and 20 (95%) had a partial response. Of the 12 patients treated after first relapse, two (17%) had a complete response and 10 (83%) had partial response after induction.
RIT consolidation was performed 3-5 weeks after the last chemotherapy cycle. Patients with cytopenias after chemotherapy could wait an additional 3 weeks, during which they would receive a bridging dose of rituximab at the standard 375 mg/m2 dose. The patients received two doses of rituximab 250 mg/m2 administered 7 days then 24 hours prior to intravenous injection of 90Y-labeled ibritumomab tiuxetan. The radiation doses delivered were 0.4 mCi/kg for patients with normal platelet counts and 0.3 mCi/kg for those with platelet counts from 100,000 to 150,000 cells/mm3. The maximum dose was 32.0 mCi.
The longest follow-up was out to slightly more than 8 years.
For the patients who received RIT after first-line induction, the complete response rate was 91%, and the partial response rate was 9%, compared with 41% complete response and 59% partial response after induction. In this group, the median progression-free survival was 3.3 years, and the median overall survival was 6.5 years.
For the patients who received RIT consolidation after first relapse and second chemotherapy regimen, the complete response rate was 75% and the partial response rate was 25%, compared with 17% and 83% at the end of second induction therapy. In this group, the median progression-free survival was 1.8 years (P less than .05, compared with patients treated after first-line responses), and the median overall survival was 2.2 years (P less than .05).
At 8 years of follow-up, 30% of patients who received RIT consolidation following first-line therapy were alive.
Adverse events included cytopenias in the majority of patients (77%), which were grade 1 or 2 in severity in 43% and grade 3 or 4 in 34%. Grade 3 or 4 thrombocytopenia and leukopenia occurred more frequently in patients treated with fludarabine-based regimens, and the thrombocytopenias in these patients lasted longer and required more platelet transfusions than those in CHOP- or CVP-treated patients. Two patients who underwent RIT following FCM induction died from prolonged thrombocytopenia, resulting in hemorrhagic strokes.
Among all patients, 22 patients developed infections following RIT consolidation. Five patients, all of whom had received fludarabine, required hospitalization for the treatment of the infections. There were no infection-related deaths, however.
Five patients developed the myelodysplastic syndrome, with a median onset time of 26 months. Of these patients, four had received fludarabine, and one had undergone a prior ASCT.
The trial was sponsored by Schering AG. Dr. Jurczak reported speakers bureau participation and research funding from multiple companies, not including Schering AG.
SOURCE: Jurczak W et al. Leuk Lymphoma. 2019 Apr 9. doi: 10.1080/10428194.2019.1602261.
FROM LEUKEMIA & LYMPHOMA
Creating CAR T-cell therapies for T-cell malignancies
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM ALF 2019
Dr. Louis Weiner: AACR presentations highlight new “transformative strategies”
ATLANTA – Several studies featured during a press briefing at the annual meeting of the American Association for Cancer Research highlight the types of “transformative strategies” currently being developed and implemented, according to Louis Weiner, MD.
“Had this been the AACR [meeting] 20 years ago ... each one of them would have been a main plenary presentation and would have been the talk of the meeting,” Dr. Weiner, director of the Georgetown Lombardi Cancer Center at Georgetown University, Washington, and press briefing moderator, said of the findings.
While they are well accepted as being high quality presentations of great value, they don’t cause the same amount of stir, he said, adding: “I wouldn’t say we’re jaded, but we’ve come to the point where we almost expect great results at these meetings, and isn’t that wonderful?”
In this video interview he discussed the findings of two of the studies, including the phase 2 UNITY-NHL study and a preclinical Lynch syndrome mouse model used to develop a potential cancer preventive vaccine.
The Lynch syndrome data “suggest the strong possibility that we might be able to immunize people and combine that treatment with standard nonsteroidal anti-inflammatory agents such as naproxen to delay or reduce the impact of Lynch syndrome.”
“This set of findings ... opens the door to investigators in many different areas of cancer research to explore whether or not there are common frameshift mutations that might create novel neoantigens that we can go after with vaccines – be they for therapeutic benefit or for prevention,” he said.
The UNITY-NHL study, which showed that umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, suggests “it’s quite possible that [the phosphoinositide 3-kinase delta inhibitor] is going to become a very important element in the treatment of patients with marginal zone lymphomas, and obviously it can be then used in earlier stages of diseases since it’s well tolerated, and it may well have useful activity in other B-cell malignancies,” he said.
Dr. Weiner reported having no relevant disclosures.
ATLANTA – Several studies featured during a press briefing at the annual meeting of the American Association for Cancer Research highlight the types of “transformative strategies” currently being developed and implemented, according to Louis Weiner, MD.
“Had this been the AACR [meeting] 20 years ago ... each one of them would have been a main plenary presentation and would have been the talk of the meeting,” Dr. Weiner, director of the Georgetown Lombardi Cancer Center at Georgetown University, Washington, and press briefing moderator, said of the findings.
While they are well accepted as being high quality presentations of great value, they don’t cause the same amount of stir, he said, adding: “I wouldn’t say we’re jaded, but we’ve come to the point where we almost expect great results at these meetings, and isn’t that wonderful?”
In this video interview he discussed the findings of two of the studies, including the phase 2 UNITY-NHL study and a preclinical Lynch syndrome mouse model used to develop a potential cancer preventive vaccine.
The Lynch syndrome data “suggest the strong possibility that we might be able to immunize people and combine that treatment with standard nonsteroidal anti-inflammatory agents such as naproxen to delay or reduce the impact of Lynch syndrome.”
“This set of findings ... opens the door to investigators in many different areas of cancer research to explore whether or not there are common frameshift mutations that might create novel neoantigens that we can go after with vaccines – be they for therapeutic benefit or for prevention,” he said.
The UNITY-NHL study, which showed that umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, suggests “it’s quite possible that [the phosphoinositide 3-kinase delta inhibitor] is going to become a very important element in the treatment of patients with marginal zone lymphomas, and obviously it can be then used in earlier stages of diseases since it’s well tolerated, and it may well have useful activity in other B-cell malignancies,” he said.
Dr. Weiner reported having no relevant disclosures.
ATLANTA – Several studies featured during a press briefing at the annual meeting of the American Association for Cancer Research highlight the types of “transformative strategies” currently being developed and implemented, according to Louis Weiner, MD.
“Had this been the AACR [meeting] 20 years ago ... each one of them would have been a main plenary presentation and would have been the talk of the meeting,” Dr. Weiner, director of the Georgetown Lombardi Cancer Center at Georgetown University, Washington, and press briefing moderator, said of the findings.
While they are well accepted as being high quality presentations of great value, they don’t cause the same amount of stir, he said, adding: “I wouldn’t say we’re jaded, but we’ve come to the point where we almost expect great results at these meetings, and isn’t that wonderful?”
In this video interview he discussed the findings of two of the studies, including the phase 2 UNITY-NHL study and a preclinical Lynch syndrome mouse model used to develop a potential cancer preventive vaccine.
The Lynch syndrome data “suggest the strong possibility that we might be able to immunize people and combine that treatment with standard nonsteroidal anti-inflammatory agents such as naproxen to delay or reduce the impact of Lynch syndrome.”
“This set of findings ... opens the door to investigators in many different areas of cancer research to explore whether or not there are common frameshift mutations that might create novel neoantigens that we can go after with vaccines – be they for therapeutic benefit or for prevention,” he said.
The UNITY-NHL study, which showed that umbralisib is active and well tolerated as single-agent therapy in patients with relapsed or refractory marginal zone lymphoma, suggests “it’s quite possible that [the phosphoinositide 3-kinase delta inhibitor] is going to become a very important element in the treatment of patients with marginal zone lymphomas, and obviously it can be then used in earlier stages of diseases since it’s well tolerated, and it may well have useful activity in other B-cell malignancies,” he said.
Dr. Weiner reported having no relevant disclosures.
REPORTING FROM AACR
In situ vaccination produced responses in indolent NHL
A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.
The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).
ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.
In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.
“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”
Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
Preclinical results
Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.
Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.
However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.
The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
Clinical results
Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.
The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).
“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.
At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.
ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.
This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.
SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.
A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.
The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).
ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.
In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.
“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”
Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
Preclinical results
Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.
Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.
However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.
The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
Clinical results
Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.
The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).
“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.
At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.
ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.
This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.
SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.
A three-pronged treatment approach can produce responses in indolent non-Hodgkin lymphoma (iNHL), according to research published in Nature Medicine.
The approach – “in situ vaccination (ISV)” – involves intratumoral injections of Fms-like tyrosine kinase 3 ligand (Flt3L), local radiotherapy, and intratumoral injections of a TLR3 agonist (poly-ICLC).
ISV produced responses in patients with iNHL, prompting regression of tumors that were directly targeted with ISV, as well as untreated tumors.
In preclinical experiments, ISV induced tumor regression in mice but also overcame resistance to PD1 inhibition. This result led researchers to initiate a trial testing ISV in combination with pembrolizumab in patients with lymphoma and solid tumors.
“We discovered why some tumors do not respond to PD1 blockade: insufficient dendritic cells (DCs) and cross-presentation,” lead study author Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai, New York, said in an interview. “We developed a treatment, in situ vaccination (ISV), which brings DCs to the tumor, loads them with tumor antigens, and activates the DCs.”
Specifically, the researchers found that injecting Flt3L into a tumor recruits intratumoral DCs, local radiotherapy loads the DCs with tumor-associated antigens, and poly-ICLC activates DCs. This approach produced responses in mouse models of lymphoma and patients with iNHL.
Preclinical results
Dr. Brody and his colleagues tested ISV in A20 tumor-bearing mice. The mice received intratumoral injections of Flt3L, followed by local radiotherapy and poly-ICLC.
Tumor regression occurred within days of radiotherapy. About 40% of mice experienced tumor-free survival of at least 3 months, although most tumors recurred within 4 weeks of ISV administration.
However, the researchers observed increased PD1 and PD-L1 expression in ISV-treated mice, so the team theorized that an anti-PD1 monoclonal antibody (RMP1-14) could improve the efficacy of ISV.
The researchers found that ISV plus RMP1-14 delayed tumor growth when compared with ISV alone, and the rate of durable remissions increased from about 40% to about 80%.
Clinical results
Dr. Brody and his colleagues also tested ISV in a clinical trial. That trial included 11 iNHL patients – 9 with follicular lymphoma, 1 with marginal zone lymphoma, and 1 with small lymphocytic lymphoma.
The patients received nine daily injections of Flt3L (25 mcg/kg) into a target lesion, then two doses of radiation (2 Gy) to the same lesion, and eight intratumoral injections of poly-ICLC (2 mg).
“We ... have observed dramatic clinical responses; i.e., we administer ISV at one tumor site, and tumors throughout the body regress,” Dr. Brody said.
At the target lesion, there were two complete responses, six partial responses, and three cases of stable disease. At nontarget lesions, there was one complete response, two partial responses, six cases of stable disease, and two cases of progression.
ISV was considered well tolerated. One patient had grade 2 fever, three had grade 1 fever, and nine had grade 1 flu-like symptoms. Two patients did not have any adverse events.
This research was supported by Merck, Celldex Therapeutics, Oncovir, and Genentech. The authors reported relationships with Acerta Pharma, Bristol Myers Squibb, Genentech, Gilead Sciences, Seattle Genetics, Pharmacyclics, Celgene, Celldex Therapeutics, and Oncovir.
SOURCE: Hammerich L et al. Nat Med. 2019 Apr 8. doi: 10.1038/s41591-019-0410-x.
FROM NATURE MEDICINE