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Overcoming TP53 mutation proves difficult in MCL
, new findings suggest.
“TP53 mutated MCL remains a major challenge, and our results underline the importance of molecular profiling, including TP53 status, in future trials exploring novel agents,” wrote Christian Winther Eskelund, MD, of Rigshospitalet in Copenhagen, and his colleagues. The findings were published in Haematologica.
The researchers noted that the results will need validation in a larger cohort of patients.
They performed an analysis of 50 MCL patients who enrolled in the Nordic MCL4 trial between 2009 and 2013. Patients were either over age 65 years or were younger but unfit for autologous stem cell transplantation. Despite the addition of lenalidomide to the chemoimmunotherapy regimen, patients with TP53 mutations had worse overall and progression-free survival and were significantly quicker to experience relapse.
After a median follow up of 47 months, median overall survival was 25 months for patients with TP53 mutations, compared with 69 months for those without (P less than .0001). Similarly, median progression-free survival was 10 months in patients with the mutation, compared with 42 months in patients without it (P = .001). Time to relapse was a median of 10 months in these mutated patients, compared with 58 months for unmutated MCL patients (P less than .0001).
TP53 mutations were identified in six patients (14%), one of whom withdrew consent at day 28 of the study. Of the remaining patients with mutations, all of them either progressed or relapsed during the study and none were alive at the most recent follow-up. During the study, patients received an induction phase of six cycles of lenalidomide plus bendamustine-rituximab (weeks 1-24), followed by a maintenance phase of lenalidomide (weeks 25-56).
SOURCE: Eskelund CW et al. Haematologica. 2018 May 24. doi: 10.3324/haematol.2018.194399.
, new findings suggest.
“TP53 mutated MCL remains a major challenge, and our results underline the importance of molecular profiling, including TP53 status, in future trials exploring novel agents,” wrote Christian Winther Eskelund, MD, of Rigshospitalet in Copenhagen, and his colleagues. The findings were published in Haematologica.
The researchers noted that the results will need validation in a larger cohort of patients.
They performed an analysis of 50 MCL patients who enrolled in the Nordic MCL4 trial between 2009 and 2013. Patients were either over age 65 years or were younger but unfit for autologous stem cell transplantation. Despite the addition of lenalidomide to the chemoimmunotherapy regimen, patients with TP53 mutations had worse overall and progression-free survival and were significantly quicker to experience relapse.
After a median follow up of 47 months, median overall survival was 25 months for patients with TP53 mutations, compared with 69 months for those without (P less than .0001). Similarly, median progression-free survival was 10 months in patients with the mutation, compared with 42 months in patients without it (P = .001). Time to relapse was a median of 10 months in these mutated patients, compared with 58 months for unmutated MCL patients (P less than .0001).
TP53 mutations were identified in six patients (14%), one of whom withdrew consent at day 28 of the study. Of the remaining patients with mutations, all of them either progressed or relapsed during the study and none were alive at the most recent follow-up. During the study, patients received an induction phase of six cycles of lenalidomide plus bendamustine-rituximab (weeks 1-24), followed by a maintenance phase of lenalidomide (weeks 25-56).
SOURCE: Eskelund CW et al. Haematologica. 2018 May 24. doi: 10.3324/haematol.2018.194399.
, new findings suggest.
“TP53 mutated MCL remains a major challenge, and our results underline the importance of molecular profiling, including TP53 status, in future trials exploring novel agents,” wrote Christian Winther Eskelund, MD, of Rigshospitalet in Copenhagen, and his colleagues. The findings were published in Haematologica.
The researchers noted that the results will need validation in a larger cohort of patients.
They performed an analysis of 50 MCL patients who enrolled in the Nordic MCL4 trial between 2009 and 2013. Patients were either over age 65 years or were younger but unfit for autologous stem cell transplantation. Despite the addition of lenalidomide to the chemoimmunotherapy regimen, patients with TP53 mutations had worse overall and progression-free survival and were significantly quicker to experience relapse.
After a median follow up of 47 months, median overall survival was 25 months for patients with TP53 mutations, compared with 69 months for those without (P less than .0001). Similarly, median progression-free survival was 10 months in patients with the mutation, compared with 42 months in patients without it (P = .001). Time to relapse was a median of 10 months in these mutated patients, compared with 58 months for unmutated MCL patients (P less than .0001).
TP53 mutations were identified in six patients (14%), one of whom withdrew consent at day 28 of the study. Of the remaining patients with mutations, all of them either progressed or relapsed during the study and none were alive at the most recent follow-up. During the study, patients received an induction phase of six cycles of lenalidomide plus bendamustine-rituximab (weeks 1-24), followed by a maintenance phase of lenalidomide (weeks 25-56).
SOURCE: Eskelund CW et al. Haematologica. 2018 May 24. doi: 10.3324/haematol.2018.194399.
FROM HAEMATOLOGICA
Adding bortezomib does not improve MCL outcomes
Bortezomib added to an alternating chemoimmunotherapy regimen did not improve time to treatment failure in patients with newly diagnosed mantle cell lymphoma (MCL), results of a phase 2 study have suggested.
Response rates and time to treatment failure were similar to what has been seen historically without the addition of bortezomib, according to study investigator Jorge E. Romaguera, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
The phase 2 study included 95 patients with newly diagnosed MCL treated with alternating cycles of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD) and bortezomib added to rituximab plus high-dose methotrexate and high-dose cytarabine (BzR-MA).
Of 87 patients evaluable for response, alternating BzR-hyperCVAD/BzR-MA resulted in an overall response rate of 100% and a complete response rate of 82%, Dr. Romaguera and his colleagues reported in the journal Cancer. At a median follow-up of 44 months, median time to treatment failure was 55 months, and median overall survival had not yet been reached, according to the report.
Dr. Romaguera and his coauthors compared these results with those from a previous study of alternating R-hyperCVAD/R-MA, in which the median time to treatment failure was 56.4 months. “This suggests that the addition of bortezomib does not improve the outcome,” they wrote in the current report.
Although more follow-up is needed, the landscape of MCL treatment is changing quickly, they added. In particular, lenalidomide and ibrutinib, already approved for relapsed/refractory MCL, are now being evaluated as part of first-line MCL regimens. “These drugs will offer strategies of either consolidation or maintenance after induction and will hopefully help continue to improve the duration of the initial response and the overall outcome,” the researchers wrote.
In the current phase 2 study, the fact that 100% of patients achieved complete response suggested that relapses come from minimal residual disease, which “has clearly become a clinical factor for the outcomes of patients with MCL and will likely become the next endpoint,” they wrote.
The researchers reported having no financial disclosures related to the study, which was supported by Takeda Oncology.
SOURCE: Romaguera JE et al. Cancer. 2018 May 3. doi: 10.1002/cncr.31361.
Bortezomib added to an alternating chemoimmunotherapy regimen did not improve time to treatment failure in patients with newly diagnosed mantle cell lymphoma (MCL), results of a phase 2 study have suggested.
Response rates and time to treatment failure were similar to what has been seen historically without the addition of bortezomib, according to study investigator Jorge E. Romaguera, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
The phase 2 study included 95 patients with newly diagnosed MCL treated with alternating cycles of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD) and bortezomib added to rituximab plus high-dose methotrexate and high-dose cytarabine (BzR-MA).
Of 87 patients evaluable for response, alternating BzR-hyperCVAD/BzR-MA resulted in an overall response rate of 100% and a complete response rate of 82%, Dr. Romaguera and his colleagues reported in the journal Cancer. At a median follow-up of 44 months, median time to treatment failure was 55 months, and median overall survival had not yet been reached, according to the report.
Dr. Romaguera and his coauthors compared these results with those from a previous study of alternating R-hyperCVAD/R-MA, in which the median time to treatment failure was 56.4 months. “This suggests that the addition of bortezomib does not improve the outcome,” they wrote in the current report.
Although more follow-up is needed, the landscape of MCL treatment is changing quickly, they added. In particular, lenalidomide and ibrutinib, already approved for relapsed/refractory MCL, are now being evaluated as part of first-line MCL regimens. “These drugs will offer strategies of either consolidation or maintenance after induction and will hopefully help continue to improve the duration of the initial response and the overall outcome,” the researchers wrote.
In the current phase 2 study, the fact that 100% of patients achieved complete response suggested that relapses come from minimal residual disease, which “has clearly become a clinical factor for the outcomes of patients with MCL and will likely become the next endpoint,” they wrote.
The researchers reported having no financial disclosures related to the study, which was supported by Takeda Oncology.
SOURCE: Romaguera JE et al. Cancer. 2018 May 3. doi: 10.1002/cncr.31361.
Bortezomib added to an alternating chemoimmunotherapy regimen did not improve time to treatment failure in patients with newly diagnosed mantle cell lymphoma (MCL), results of a phase 2 study have suggested.
Response rates and time to treatment failure were similar to what has been seen historically without the addition of bortezomib, according to study investigator Jorge E. Romaguera, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
The phase 2 study included 95 patients with newly diagnosed MCL treated with alternating cycles of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD) and bortezomib added to rituximab plus high-dose methotrexate and high-dose cytarabine (BzR-MA).
Of 87 patients evaluable for response, alternating BzR-hyperCVAD/BzR-MA resulted in an overall response rate of 100% and a complete response rate of 82%, Dr. Romaguera and his colleagues reported in the journal Cancer. At a median follow-up of 44 months, median time to treatment failure was 55 months, and median overall survival had not yet been reached, according to the report.
Dr. Romaguera and his coauthors compared these results with those from a previous study of alternating R-hyperCVAD/R-MA, in which the median time to treatment failure was 56.4 months. “This suggests that the addition of bortezomib does not improve the outcome,” they wrote in the current report.
Although more follow-up is needed, the landscape of MCL treatment is changing quickly, they added. In particular, lenalidomide and ibrutinib, already approved for relapsed/refractory MCL, are now being evaluated as part of first-line MCL regimens. “These drugs will offer strategies of either consolidation or maintenance after induction and will hopefully help continue to improve the duration of the initial response and the overall outcome,” the researchers wrote.
In the current phase 2 study, the fact that 100% of patients achieved complete response suggested that relapses come from minimal residual disease, which “has clearly become a clinical factor for the outcomes of patients with MCL and will likely become the next endpoint,” they wrote.
The researchers reported having no financial disclosures related to the study, which was supported by Takeda Oncology.
SOURCE: Romaguera JE et al. Cancer. 2018 May 3. doi: 10.1002/cncr.31361.
FROM CANCER
Key clinical point:
Major finding: Rates of overall and complete response were 100% and 82%, respectively, while time to treatment failure was 55 months.
Study details: A phase 2 trial that included 95 patients treated with alternating cycles of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR-hyperCVAD) and bortezomib added to rituximab plus high-dose methotrexate and high-dose cytarabine (BzR-MA).
Disclosures: The study was supported by Takeda Oncology. The researchers reported having no financial disclosures related to the study.
Source: Romaguera JE et al. Cancer. 2018 May 3. doi: 10.1002/cncr.31361
In young MCL patients, optimal treatment may vary
, according to a recent review published in Best Practice & Research Clinical Haematology.
Use of high-dose cytarabine plus rituximab as frontline treatment is well established, with median overall survival now exceeding 10 years, said Rory McCulloch, MD, and Simon Rule, MD, of the department of Haematology, Derriford Hospital, Plymouth, England. However, there is no proven benefit to conventional therapy in patients with asymptomatic, non-bulky disease, making a watch-and-wait strategy appropriate for these patients, the authors said.
On the opposite end of the spectrum there is a subgroup of patients characterized by TP53 mutations and poor prognostic index scores that have poor outcomes in spite of conventional therapy.
These patients might have improved outcomes either with early allogeneic haematopoietic cell transplantation (allo-HCT), or, especially, clinical trials of novel agents in the upfront setting, the authors noted.
“There are a host of exciting novel agents, most prominently the BTK inhibitors, that are game changing with respect to their activity,” wrote Dr. McCulloch and Dr. Rule. “Based on the long-term results seen with conventional therapy, it is premature to be considering such new drugs in the frontline setting outside the context of a clinical trial, but it is hard to believe they will not become incorporated into treatment protocols in the future.”
Watch-and-wait treatment strategies for lower-risk patients are supported by the results of two single-center, retrospective studies published in 2009 that suggest the practice has no adverse impact on overall survival. More recent registry studies, published in 2016 and 2017, have shown that a significant proportion of patients can be managed according to the watch-and-wait strategy.
Although it’s been challenging to precisely define the group of patients for whom watch-and-wait is appropriate, enrollment criteria for studies have generally specified that patients be asymptomatic with non-bulky disease and non-blastoid morphology, they said.
For the minority of patients presenting with high-risk disease, allo-HCT may improve outcomes, according to Dr. McCulloch and Dr. Rule. One prospective study evaluating allogeneic transplants in frontline therapy showed favorable outcomes in younger patients, although few high-risk patients were enrolled.
However, a second prospective study of allo-HCT, involving 25 patients with untreated MCL in the United Kingdom, demonstrated a 2-year overall survival of 80%. “Although immature, the results are encouraging and provide data to support frontline allogeneic transplant for some patients,” Dr. McCulloch and Dr. Rule said in a comment on that study.
Novel agent studies have produced mixed results in treatment settings relevant to younger, high-risk MCL patients, though key trials are ongoing that could change practice.
One phase 2 study is evaluating obinituzumab, the fully humanized anti-CD20, as part of MCL induction and maintenance. Results of that study could challenge the role of rituximab in maintenance, the review authors noted. Likewise, the immune modulator lenalidomide has been evaluated as maintenance in an Italian phase 3 trial that recently closed to recruitment.
BTK inhibitors represent a “step change” in the management of MCL, according to the authors of this review.
“It has become clear that earlier use of ibrutinib leads to an improved outcome [in MCL] and it is logical to extend this into frontline treatment,” they wrote.
A randomized phase 3, multinational trial known as TRIANGLE, now open to recruitment, is designed to evaluate use of ibrutinib in both induction and maintenance. Investigators plan to enroll 870 patients into the three-arm study, which will also evaluate the use of ibrutinib as part of induction, but with no autologous stem cell transplant.
“The trial is the first to randomize to a non-ASCT arm since the introduction of rituximab and cytarabine to the induction regimen and the results have the potential to significantly reduce chemotherapy intensity and toxicity,” the authors said.
Dr. Rule reported consulting for Pharmacyclics, Napp, Sunesis, Acerta Pharma, Kite, AstraZeneca, Roche, Janssen, and Celgene, and research funding from Janssen, Celgene, and GSK. Dr. McCulloch reported having no financial disclosures.
SOURCE: McCulloch R et al. Best Pract Res Clin Haematol. 2018 Mar;31(1):90-8.
, according to a recent review published in Best Practice & Research Clinical Haematology.
Use of high-dose cytarabine plus rituximab as frontline treatment is well established, with median overall survival now exceeding 10 years, said Rory McCulloch, MD, and Simon Rule, MD, of the department of Haematology, Derriford Hospital, Plymouth, England. However, there is no proven benefit to conventional therapy in patients with asymptomatic, non-bulky disease, making a watch-and-wait strategy appropriate for these patients, the authors said.
On the opposite end of the spectrum there is a subgroup of patients characterized by TP53 mutations and poor prognostic index scores that have poor outcomes in spite of conventional therapy.
These patients might have improved outcomes either with early allogeneic haematopoietic cell transplantation (allo-HCT), or, especially, clinical trials of novel agents in the upfront setting, the authors noted.
“There are a host of exciting novel agents, most prominently the BTK inhibitors, that are game changing with respect to their activity,” wrote Dr. McCulloch and Dr. Rule. “Based on the long-term results seen with conventional therapy, it is premature to be considering such new drugs in the frontline setting outside the context of a clinical trial, but it is hard to believe they will not become incorporated into treatment protocols in the future.”
Watch-and-wait treatment strategies for lower-risk patients are supported by the results of two single-center, retrospective studies published in 2009 that suggest the practice has no adverse impact on overall survival. More recent registry studies, published in 2016 and 2017, have shown that a significant proportion of patients can be managed according to the watch-and-wait strategy.
Although it’s been challenging to precisely define the group of patients for whom watch-and-wait is appropriate, enrollment criteria for studies have generally specified that patients be asymptomatic with non-bulky disease and non-blastoid morphology, they said.
For the minority of patients presenting with high-risk disease, allo-HCT may improve outcomes, according to Dr. McCulloch and Dr. Rule. One prospective study evaluating allogeneic transplants in frontline therapy showed favorable outcomes in younger patients, although few high-risk patients were enrolled.
However, a second prospective study of allo-HCT, involving 25 patients with untreated MCL in the United Kingdom, demonstrated a 2-year overall survival of 80%. “Although immature, the results are encouraging and provide data to support frontline allogeneic transplant for some patients,” Dr. McCulloch and Dr. Rule said in a comment on that study.
Novel agent studies have produced mixed results in treatment settings relevant to younger, high-risk MCL patients, though key trials are ongoing that could change practice.
One phase 2 study is evaluating obinituzumab, the fully humanized anti-CD20, as part of MCL induction and maintenance. Results of that study could challenge the role of rituximab in maintenance, the review authors noted. Likewise, the immune modulator lenalidomide has been evaluated as maintenance in an Italian phase 3 trial that recently closed to recruitment.
BTK inhibitors represent a “step change” in the management of MCL, according to the authors of this review.
“It has become clear that earlier use of ibrutinib leads to an improved outcome [in MCL] and it is logical to extend this into frontline treatment,” they wrote.
A randomized phase 3, multinational trial known as TRIANGLE, now open to recruitment, is designed to evaluate use of ibrutinib in both induction and maintenance. Investigators plan to enroll 870 patients into the three-arm study, which will also evaluate the use of ibrutinib as part of induction, but with no autologous stem cell transplant.
“The trial is the first to randomize to a non-ASCT arm since the introduction of rituximab and cytarabine to the induction regimen and the results have the potential to significantly reduce chemotherapy intensity and toxicity,” the authors said.
Dr. Rule reported consulting for Pharmacyclics, Napp, Sunesis, Acerta Pharma, Kite, AstraZeneca, Roche, Janssen, and Celgene, and research funding from Janssen, Celgene, and GSK. Dr. McCulloch reported having no financial disclosures.
SOURCE: McCulloch R et al. Best Pract Res Clin Haematol. 2018 Mar;31(1):90-8.
, according to a recent review published in Best Practice & Research Clinical Haematology.
Use of high-dose cytarabine plus rituximab as frontline treatment is well established, with median overall survival now exceeding 10 years, said Rory McCulloch, MD, and Simon Rule, MD, of the department of Haematology, Derriford Hospital, Plymouth, England. However, there is no proven benefit to conventional therapy in patients with asymptomatic, non-bulky disease, making a watch-and-wait strategy appropriate for these patients, the authors said.
On the opposite end of the spectrum there is a subgroup of patients characterized by TP53 mutations and poor prognostic index scores that have poor outcomes in spite of conventional therapy.
These patients might have improved outcomes either with early allogeneic haematopoietic cell transplantation (allo-HCT), or, especially, clinical trials of novel agents in the upfront setting, the authors noted.
“There are a host of exciting novel agents, most prominently the BTK inhibitors, that are game changing with respect to their activity,” wrote Dr. McCulloch and Dr. Rule. “Based on the long-term results seen with conventional therapy, it is premature to be considering such new drugs in the frontline setting outside the context of a clinical trial, but it is hard to believe they will not become incorporated into treatment protocols in the future.”
Watch-and-wait treatment strategies for lower-risk patients are supported by the results of two single-center, retrospective studies published in 2009 that suggest the practice has no adverse impact on overall survival. More recent registry studies, published in 2016 and 2017, have shown that a significant proportion of patients can be managed according to the watch-and-wait strategy.
Although it’s been challenging to precisely define the group of patients for whom watch-and-wait is appropriate, enrollment criteria for studies have generally specified that patients be asymptomatic with non-bulky disease and non-blastoid morphology, they said.
For the minority of patients presenting with high-risk disease, allo-HCT may improve outcomes, according to Dr. McCulloch and Dr. Rule. One prospective study evaluating allogeneic transplants in frontline therapy showed favorable outcomes in younger patients, although few high-risk patients were enrolled.
However, a second prospective study of allo-HCT, involving 25 patients with untreated MCL in the United Kingdom, demonstrated a 2-year overall survival of 80%. “Although immature, the results are encouraging and provide data to support frontline allogeneic transplant for some patients,” Dr. McCulloch and Dr. Rule said in a comment on that study.
Novel agent studies have produced mixed results in treatment settings relevant to younger, high-risk MCL patients, though key trials are ongoing that could change practice.
One phase 2 study is evaluating obinituzumab, the fully humanized anti-CD20, as part of MCL induction and maintenance. Results of that study could challenge the role of rituximab in maintenance, the review authors noted. Likewise, the immune modulator lenalidomide has been evaluated as maintenance in an Italian phase 3 trial that recently closed to recruitment.
BTK inhibitors represent a “step change” in the management of MCL, according to the authors of this review.
“It has become clear that earlier use of ibrutinib leads to an improved outcome [in MCL] and it is logical to extend this into frontline treatment,” they wrote.
A randomized phase 3, multinational trial known as TRIANGLE, now open to recruitment, is designed to evaluate use of ibrutinib in both induction and maintenance. Investigators plan to enroll 870 patients into the three-arm study, which will also evaluate the use of ibrutinib as part of induction, but with no autologous stem cell transplant.
“The trial is the first to randomize to a non-ASCT arm since the introduction of rituximab and cytarabine to the induction regimen and the results have the potential to significantly reduce chemotherapy intensity and toxicity,” the authors said.
Dr. Rule reported consulting for Pharmacyclics, Napp, Sunesis, Acerta Pharma, Kite, AstraZeneca, Roche, Janssen, and Celgene, and research funding from Janssen, Celgene, and GSK. Dr. McCulloch reported having no financial disclosures.
SOURCE: McCulloch R et al. Best Pract Res Clin Haematol. 2018 Mar;31(1):90-8.
FROM BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY
PDPK1 could be novel target in MCL
Researchers may have found a new therapeutic approach for treating mantle cell lymphoma (MCL) by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1).
Saori Maegawa and colleagues at Kyoto Prefectural University of Medicine in Japan, evaluated PDPK1 activity in patient-derived primary B-cell lymphoma cells by immunohistochemical staining of p-PDPK1Ser241 (p-PDPK1) in tissue specimens from seven patients with MCL, six patients with diffuse large B-cell lymphoma, and five patients with follicular lymphoma. All specimens were biopsied at initial diagnosis, before starting treatment.
“Our study showed that PDPK1 inhibition caused inactivation of RSK2-NTKD, as well as the decrease of total RSK2 protein, but not of AKT, in MCL-derived cells,” the researchers wrote in Experimental Hematology. “This implies that RSK2 activity is mainly regulated by PDPK1 at both the transcriptional expression and post-translational levels, but AKT activity is regulated by a signaling pathway that does not interact with a PDPK1-mediated pathway in MCL.”
If a PDPK1 inhibitor is pursued as clinical target, the researchers said careful monitoring for hyperglycemia may be required since impaired glucose metabolism is commonly seen with AKT inhibitors. Future research in MCL could also be directed toward the targeting of RSK2-NTKD, the researchers wrote.
SOURCE: Maegawa S et al. Exp Hematol. 2018 Mar;59:72-81.e2.
Researchers may have found a new therapeutic approach for treating mantle cell lymphoma (MCL) by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1).
Saori Maegawa and colleagues at Kyoto Prefectural University of Medicine in Japan, evaluated PDPK1 activity in patient-derived primary B-cell lymphoma cells by immunohistochemical staining of p-PDPK1Ser241 (p-PDPK1) in tissue specimens from seven patients with MCL, six patients with diffuse large B-cell lymphoma, and five patients with follicular lymphoma. All specimens were biopsied at initial diagnosis, before starting treatment.
“Our study showed that PDPK1 inhibition caused inactivation of RSK2-NTKD, as well as the decrease of total RSK2 protein, but not of AKT, in MCL-derived cells,” the researchers wrote in Experimental Hematology. “This implies that RSK2 activity is mainly regulated by PDPK1 at both the transcriptional expression and post-translational levels, but AKT activity is regulated by a signaling pathway that does not interact with a PDPK1-mediated pathway in MCL.”
If a PDPK1 inhibitor is pursued as clinical target, the researchers said careful monitoring for hyperglycemia may be required since impaired glucose metabolism is commonly seen with AKT inhibitors. Future research in MCL could also be directed toward the targeting of RSK2-NTKD, the researchers wrote.
SOURCE: Maegawa S et al. Exp Hematol. 2018 Mar;59:72-81.e2.
Researchers may have found a new therapeutic approach for treating mantle cell lymphoma (MCL) by targeting 3-phosphoinositide-dependent protein kinase 1 (PDPK1).
Saori Maegawa and colleagues at Kyoto Prefectural University of Medicine in Japan, evaluated PDPK1 activity in patient-derived primary B-cell lymphoma cells by immunohistochemical staining of p-PDPK1Ser241 (p-PDPK1) in tissue specimens from seven patients with MCL, six patients with diffuse large B-cell lymphoma, and five patients with follicular lymphoma. All specimens were biopsied at initial diagnosis, before starting treatment.
“Our study showed that PDPK1 inhibition caused inactivation of RSK2-NTKD, as well as the decrease of total RSK2 protein, but not of AKT, in MCL-derived cells,” the researchers wrote in Experimental Hematology. “This implies that RSK2 activity is mainly regulated by PDPK1 at both the transcriptional expression and post-translational levels, but AKT activity is regulated by a signaling pathway that does not interact with a PDPK1-mediated pathway in MCL.”
If a PDPK1 inhibitor is pursued as clinical target, the researchers said careful monitoring for hyperglycemia may be required since impaired glucose metabolism is commonly seen with AKT inhibitors. Future research in MCL could also be directed toward the targeting of RSK2-NTKD, the researchers wrote.
SOURCE: Maegawa S et al. Exp Hematol. 2018 Mar;59:72-81.e2.
FROM EXPERIMENTAL HEMATOLOGY
Ibrutinib plus venetoclax is active in mantle cell lymphoma
In mantle cell lymphoma (MCL), ibrutinib plus venetoclax significantly improved the complete response rate, compared with what has been previously reported for ibrutinib alone, according to results of a phase 2 study.
Clinical outcomes with the combination seem superior to previously reported results for either treatment alone, said lead investigator Constantine S. Tam, MBBS, MD, of the Peter MacCallum Cancer Centre, Melbourne, and his coinvestigators.
“The results of our study, which used a historical cohort as a control, are consistent with the notion that the combination of ibrutinib and venetoclax is highly effective in mantle-cell lymphoma,” the investigators wrote in the New England Journal of Medicine.
The BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are two of the most active agents for this B-cell cancer, investigators reported. The rationale for combining the agents is “compelling” because they affect different critical pathways in the malignant B cell.
Both agents have demonstrated complete response rates of 21% in previous studies of relapsed or refractory MCL, and preclinical studies suggest the combination of ibrutinib and venetoclax would be synergistic.
In the present single-group, phase 2 study, 24 patients with MCL (23 relapsed or refractory, 1 previously untreated) started ibrutinib 560 mg daily; at 4 weeks, venetoclax was started at a low dose and increased to 400 mg daily.
The study primary end point – complete response rate at week 16 assessed by CT – was 42%, compared with 9% for ibrutinib monotherapy in the phase 2 PCYC-1104-CA study (P less than .001).
Computed tomography assessment was used for the primary end point to allow comparison to the ibrutinib monotherapy study, which did not use positron emission tomography for restaging. “Our study was designed to have 80% power to reject a complete response rate of 9% (at a one-sided alpha level of 0.05) if the rate of complete response was at least 30%,” the investigators noted.
Complete response rate assessed by positron emission tomography at week 16 was 62%, and was 71% overall.
In all, 67% of patients had absence of minimal residual disease by flow cytometry. At 15 months, 78% of the responses were ongoing, and at 18 months, 57% of patients were alive and progression free.
“Such outcomes appear to be substantially better than those that have been reported for ibrutinib or venetoclax monotherapy,” the investigators wrote.
The combination had side effects that are “acceptable to both patients and physicians,” investigators wrote. Side effects, usually low grade, included diarrhea in 83% of patients, fatigue in 75%, and nausea or vomiting in 71%. Tumor lysis syndrome was seen in two patients.
Whether ibrutinib plus venetoclax is superior to ibrutinib alone is being formally evaluated in an ongoing phase 3 study.
Janssen and AbbVie partially funded the current phase 2 study. Dr. Tam reported financial ties to Janssen, AbbVie, and Pharmacyclics. Other study authors reported financial ties to various pharmaceutical companies.
SOURCE: Tam C et al. N Engl J Med. 2018;378:1211-23.
In mantle cell lymphoma (MCL), ibrutinib plus venetoclax significantly improved the complete response rate, compared with what has been previously reported for ibrutinib alone, according to results of a phase 2 study.
Clinical outcomes with the combination seem superior to previously reported results for either treatment alone, said lead investigator Constantine S. Tam, MBBS, MD, of the Peter MacCallum Cancer Centre, Melbourne, and his coinvestigators.
“The results of our study, which used a historical cohort as a control, are consistent with the notion that the combination of ibrutinib and venetoclax is highly effective in mantle-cell lymphoma,” the investigators wrote in the New England Journal of Medicine.
The BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are two of the most active agents for this B-cell cancer, investigators reported. The rationale for combining the agents is “compelling” because they affect different critical pathways in the malignant B cell.
Both agents have demonstrated complete response rates of 21% in previous studies of relapsed or refractory MCL, and preclinical studies suggest the combination of ibrutinib and venetoclax would be synergistic.
In the present single-group, phase 2 study, 24 patients with MCL (23 relapsed or refractory, 1 previously untreated) started ibrutinib 560 mg daily; at 4 weeks, venetoclax was started at a low dose and increased to 400 mg daily.
The study primary end point – complete response rate at week 16 assessed by CT – was 42%, compared with 9% for ibrutinib monotherapy in the phase 2 PCYC-1104-CA study (P less than .001).
Computed tomography assessment was used for the primary end point to allow comparison to the ibrutinib monotherapy study, which did not use positron emission tomography for restaging. “Our study was designed to have 80% power to reject a complete response rate of 9% (at a one-sided alpha level of 0.05) if the rate of complete response was at least 30%,” the investigators noted.
Complete response rate assessed by positron emission tomography at week 16 was 62%, and was 71% overall.
In all, 67% of patients had absence of minimal residual disease by flow cytometry. At 15 months, 78% of the responses were ongoing, and at 18 months, 57% of patients were alive and progression free.
“Such outcomes appear to be substantially better than those that have been reported for ibrutinib or venetoclax monotherapy,” the investigators wrote.
The combination had side effects that are “acceptable to both patients and physicians,” investigators wrote. Side effects, usually low grade, included diarrhea in 83% of patients, fatigue in 75%, and nausea or vomiting in 71%. Tumor lysis syndrome was seen in two patients.
Whether ibrutinib plus venetoclax is superior to ibrutinib alone is being formally evaluated in an ongoing phase 3 study.
Janssen and AbbVie partially funded the current phase 2 study. Dr. Tam reported financial ties to Janssen, AbbVie, and Pharmacyclics. Other study authors reported financial ties to various pharmaceutical companies.
SOURCE: Tam C et al. N Engl J Med. 2018;378:1211-23.
In mantle cell lymphoma (MCL), ibrutinib plus venetoclax significantly improved the complete response rate, compared with what has been previously reported for ibrutinib alone, according to results of a phase 2 study.
Clinical outcomes with the combination seem superior to previously reported results for either treatment alone, said lead investigator Constantine S. Tam, MBBS, MD, of the Peter MacCallum Cancer Centre, Melbourne, and his coinvestigators.
“The results of our study, which used a historical cohort as a control, are consistent with the notion that the combination of ibrutinib and venetoclax is highly effective in mantle-cell lymphoma,” the investigators wrote in the New England Journal of Medicine.
The BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are two of the most active agents for this B-cell cancer, investigators reported. The rationale for combining the agents is “compelling” because they affect different critical pathways in the malignant B cell.
Both agents have demonstrated complete response rates of 21% in previous studies of relapsed or refractory MCL, and preclinical studies suggest the combination of ibrutinib and venetoclax would be synergistic.
In the present single-group, phase 2 study, 24 patients with MCL (23 relapsed or refractory, 1 previously untreated) started ibrutinib 560 mg daily; at 4 weeks, venetoclax was started at a low dose and increased to 400 mg daily.
The study primary end point – complete response rate at week 16 assessed by CT – was 42%, compared with 9% for ibrutinib monotherapy in the phase 2 PCYC-1104-CA study (P less than .001).
Computed tomography assessment was used for the primary end point to allow comparison to the ibrutinib monotherapy study, which did not use positron emission tomography for restaging. “Our study was designed to have 80% power to reject a complete response rate of 9% (at a one-sided alpha level of 0.05) if the rate of complete response was at least 30%,” the investigators noted.
Complete response rate assessed by positron emission tomography at week 16 was 62%, and was 71% overall.
In all, 67% of patients had absence of minimal residual disease by flow cytometry. At 15 months, 78% of the responses were ongoing, and at 18 months, 57% of patients were alive and progression free.
“Such outcomes appear to be substantially better than those that have been reported for ibrutinib or venetoclax monotherapy,” the investigators wrote.
The combination had side effects that are “acceptable to both patients and physicians,” investigators wrote. Side effects, usually low grade, included diarrhea in 83% of patients, fatigue in 75%, and nausea or vomiting in 71%. Tumor lysis syndrome was seen in two patients.
Whether ibrutinib plus venetoclax is superior to ibrutinib alone is being formally evaluated in an ongoing phase 3 study.
Janssen and AbbVie partially funded the current phase 2 study. Dr. Tam reported financial ties to Janssen, AbbVie, and Pharmacyclics. Other study authors reported financial ties to various pharmaceutical companies.
SOURCE: Tam C et al. N Engl J Med. 2018;378:1211-23.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Dual targeting of BTK and BCL2 with ibrutinib and venetoclax may improve complete response rate versus ibrutinib alone in patients with mantle cell lymphoma.
Major finding: Complete response rate at week 16 as assessed by CT was 42%, compared with 9% with ibrutinib monotherapy in a previous study (P less than .001).
Study details: A single-group phase 2 study of daily oral ibrutinib and venetoclax in 24 patients with mantle cell lymphoma (23 relapsed or refractory, 1 previously untreated), as compared with historical controls.
Disclosures: Janssen and AbbVie partially funded the study. Dr. Tam reported financial ties to Janssen, Abbvie, and Pharmacyclics. Other study authors reported financial ties to various pharmaceutical companies.
Source: Tam C et al. N Engl J Med. 2018;378:1211-23.
Time to rethink MCL treatment, trial design
Classic mantle cell lymphoma (cMCL) has long been treated as a uniformly aggressive disease in need of similarly aggressive treatment, but that approach may be leading to overtreatment, according to one expert.
“The cMCL encompasses a broad category of lymphomas with highly variable clinical behaviors. A contemporary categorization of cMCL as a predominantly aggressive entity is misleading, as only an estimated 20% to 25% of patients with cMCL present with a symptomatic or aggressively behaving disease,” Leonid L. Yavorkovsky, MD, PhD, of the Kaiser Permanente San Jose Medical Center (Calif.), wrote in a commentary in JAMA Oncology.
While groups like the National Comprehensive Cancer Network and the European Society for Medical Oncology recommend that only older patients and those with significant comorbidities should be exempted from intensive therapy, Dr. Yavorkovsky said to identify asymptomatic patients who might be able to safely delay aggressive treatment. He also called for more risk-adapted patient assignment to cMCL clinical trials.
“The failure to recognize the erratic nature of cMCL in clinical studies may confound the outcome gains and, ultimately, undermine the ensuing treatment recommendations,” Dr. Yavorkovsky wrote.
Read his full commentary in JAMA Oncology.
mschneider@frontlinemedcom.com
SOURCE: Yavorkovsky L, JAMA Oncology. 2018 Mar 1. doi: 10.1001/jamaoncol.2017.5685.
Classic mantle cell lymphoma (cMCL) has long been treated as a uniformly aggressive disease in need of similarly aggressive treatment, but that approach may be leading to overtreatment, according to one expert.
“The cMCL encompasses a broad category of lymphomas with highly variable clinical behaviors. A contemporary categorization of cMCL as a predominantly aggressive entity is misleading, as only an estimated 20% to 25% of patients with cMCL present with a symptomatic or aggressively behaving disease,” Leonid L. Yavorkovsky, MD, PhD, of the Kaiser Permanente San Jose Medical Center (Calif.), wrote in a commentary in JAMA Oncology.
While groups like the National Comprehensive Cancer Network and the European Society for Medical Oncology recommend that only older patients and those with significant comorbidities should be exempted from intensive therapy, Dr. Yavorkovsky said to identify asymptomatic patients who might be able to safely delay aggressive treatment. He also called for more risk-adapted patient assignment to cMCL clinical trials.
“The failure to recognize the erratic nature of cMCL in clinical studies may confound the outcome gains and, ultimately, undermine the ensuing treatment recommendations,” Dr. Yavorkovsky wrote.
Read his full commentary in JAMA Oncology.
mschneider@frontlinemedcom.com
SOURCE: Yavorkovsky L, JAMA Oncology. 2018 Mar 1. doi: 10.1001/jamaoncol.2017.5685.
Classic mantle cell lymphoma (cMCL) has long been treated as a uniformly aggressive disease in need of similarly aggressive treatment, but that approach may be leading to overtreatment, according to one expert.
“The cMCL encompasses a broad category of lymphomas with highly variable clinical behaviors. A contemporary categorization of cMCL as a predominantly aggressive entity is misleading, as only an estimated 20% to 25% of patients with cMCL present with a symptomatic or aggressively behaving disease,” Leonid L. Yavorkovsky, MD, PhD, of the Kaiser Permanente San Jose Medical Center (Calif.), wrote in a commentary in JAMA Oncology.
While groups like the National Comprehensive Cancer Network and the European Society for Medical Oncology recommend that only older patients and those with significant comorbidities should be exempted from intensive therapy, Dr. Yavorkovsky said to identify asymptomatic patients who might be able to safely delay aggressive treatment. He also called for more risk-adapted patient assignment to cMCL clinical trials.
“The failure to recognize the erratic nature of cMCL in clinical studies may confound the outcome gains and, ultimately, undermine the ensuing treatment recommendations,” Dr. Yavorkovsky wrote.
Read his full commentary in JAMA Oncology.
mschneider@frontlinemedcom.com
SOURCE: Yavorkovsky L, JAMA Oncology. 2018 Mar 1. doi: 10.1001/jamaoncol.2017.5685.
FROM JAMA ONCOLOGY
Outpatient CAR T infusions feasible using liso-cel
SALT LAKE CITY – A CD19-directed 4-1BB chimeric antigen receptor (CAR) T cell product showed efficacy and a low rate of cytokine release syndrome and neurotoxicity in patients with aggressive lymphomas and poor prognoses, raising the possibility of outpatient administration and fewer hospitalization days in this high-risk group.
A total of 86 patients who received inpatient infusions of lisocabtagene maraleucel (liso-cel, also known as JCAR017) had a mean 15.6 days of hospitalization, compared with 9.3 days for 8 outpatient recipients, said Jeremy Abramson, MD, speaking at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
As of October 2017, eight patients had received liso-cel infusion as outpatients with at least 28 days of postinfusion data, Dr. Abramson said.
Although all but one required hospital admission, at a median of 5 days postinfusion (range, 4-22 days), there had been no intensive care unit admissions, and no outpatient recipients had experienced severe cytokine release syndrome (CRS) or neurotoxicity. All admitted patients presented with fever.
Among the study population, “Cytokine release syndrome was only seen in 35% of our entire dataset,” with neurologic toxicity seen in 19% of participants, Dr. Abramson said. “The majority of subjects had no CRS and no toxicity,” he said. Severe CRS occurred in 1% of the study population, and severe neurotoxicity in 12%. There were no deaths related to either complication.
Dr. Abramson reported these results from the TRANSCEND NHL 001 trial, a seamless design phase 1 pivotal trial of liso-cel enrolling patients with relapsed and refractory aggressive B cell non-Hodgkin lymphoma (NHL). Liso-cel delivers CD19-directed CD4 and CD8 CAR T cells in a 1:1 ratio, said Dr. Abramson, director of the lymphoma program at the Massachusetts General Hospital Cancer Center, Boston.
A total of 91 patients were randomized to one of the three dose-finding cohorts of the multicenter trial of liso-cel. One cohort received 5 x 107 cells in a single dose; a second cohort received the same number of cells but in two doses administered 14 days apart; the third cohort received a single dose of 1 x 108 cells.
The seamless trial design then moved to dose expansion, using the two single doses established in the dose-finding phase of the study. Ultimately, Dr. Abramson said, the third and pivotal diffuse large B-cell lymphoma (DLBCL) cohort received the higher single dose, since a dose-response relationship was seen in the earlier cohorts. No increase in cytokine release syndrome or neurotoxicity has been seen with the higher dose in patients evaluated to date.
Patients (median age, 61 years) were eligible to participate in the trial if they had relapsed or refractory DLBCL, primary mediastinal B-cell lymphoma, grade 3B follicular lymphoma, or mantle cell lymphoma. Patients with a failed prior allogeneic stem cell transplant or secondary central nervous system involvement were eligible, but all patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
As the trial moved to the core pivotal phase, eligibility requirements shifted slightly to include patients with ECOG status 0 or 1, and lymphoma diagnoses narrowed to include only DLBCL not otherwise specified (NOS), transformed follicular lymphoma, and high-grade B-cell lymphoma with double- and triple-hit cytogenetics. The core group was nearing completion of accrual at the time of the presentation, which presented preliminary results from this phase of the trial.
Among the 88 evaluable patients in the initial population with DLBCL receiving any of three dose levels, the best overall response rate (ORR) was 74% (95% confidence interval, 63%-83%); 52% of these patients achieved complete response (CR; 95% CI, 41%-63%).
For patients receiving the higher dose of liso-cel, the ORR was 81% (95% CI, 62%-94%), with a 63% CR rate (95% CI, 42%-81%), bearing out the dose-response rate that had been seen earlier in the trial, Dr. Abramson said.
The median duration of response in all TRANSCEND patients was 9.2 months; the median duration of remission has not been reached, he said. “We see evidence of durable response at 3 months in all our high-risk subsets, and that includes double- and triple-hit lymphomas, double-expresser lymphomas, patients who’ve never achieved prior complete remission, and patients with refractory disease.”
“The overall results are similarly encouraging,” Dr. Abramson said, with 86% of all patients alive at 6 months. Among the complete responders, 94% are alive at the 6-month mark. “The median duration of complete responders has not been reached in this cohort,” he said.
These results are notable, Dr. Abramson said, since about 90% of study participants have at least one disease risk factor that would predict median overall survival of 3-6 months.
During the period after leukapheresis while the CAR T cells were in production, patients could have ongoing treatment, but received PET scans to confirm disease before continuing enrollment in the trial and receiving liso-cel. The time from apheresis to product release for the pivotal cohort is now under 21 days, he said.
The study was supported by Juno Therapeutics, which plans to market liso-cel. Dr. Abramson reported ties with Celgene, Gilead, Seattle Genetics, Novartis, and Genentech.
SOURCE: Abramson J et al. Abstract 5.
SALT LAKE CITY – A CD19-directed 4-1BB chimeric antigen receptor (CAR) T cell product showed efficacy and a low rate of cytokine release syndrome and neurotoxicity in patients with aggressive lymphomas and poor prognoses, raising the possibility of outpatient administration and fewer hospitalization days in this high-risk group.
A total of 86 patients who received inpatient infusions of lisocabtagene maraleucel (liso-cel, also known as JCAR017) had a mean 15.6 days of hospitalization, compared with 9.3 days for 8 outpatient recipients, said Jeremy Abramson, MD, speaking at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
As of October 2017, eight patients had received liso-cel infusion as outpatients with at least 28 days of postinfusion data, Dr. Abramson said.
Although all but one required hospital admission, at a median of 5 days postinfusion (range, 4-22 days), there had been no intensive care unit admissions, and no outpatient recipients had experienced severe cytokine release syndrome (CRS) or neurotoxicity. All admitted patients presented with fever.
Among the study population, “Cytokine release syndrome was only seen in 35% of our entire dataset,” with neurologic toxicity seen in 19% of participants, Dr. Abramson said. “The majority of subjects had no CRS and no toxicity,” he said. Severe CRS occurred in 1% of the study population, and severe neurotoxicity in 12%. There were no deaths related to either complication.
Dr. Abramson reported these results from the TRANSCEND NHL 001 trial, a seamless design phase 1 pivotal trial of liso-cel enrolling patients with relapsed and refractory aggressive B cell non-Hodgkin lymphoma (NHL). Liso-cel delivers CD19-directed CD4 and CD8 CAR T cells in a 1:1 ratio, said Dr. Abramson, director of the lymphoma program at the Massachusetts General Hospital Cancer Center, Boston.
A total of 91 patients were randomized to one of the three dose-finding cohorts of the multicenter trial of liso-cel. One cohort received 5 x 107 cells in a single dose; a second cohort received the same number of cells but in two doses administered 14 days apart; the third cohort received a single dose of 1 x 108 cells.
The seamless trial design then moved to dose expansion, using the two single doses established in the dose-finding phase of the study. Ultimately, Dr. Abramson said, the third and pivotal diffuse large B-cell lymphoma (DLBCL) cohort received the higher single dose, since a dose-response relationship was seen in the earlier cohorts. No increase in cytokine release syndrome or neurotoxicity has been seen with the higher dose in patients evaluated to date.
Patients (median age, 61 years) were eligible to participate in the trial if they had relapsed or refractory DLBCL, primary mediastinal B-cell lymphoma, grade 3B follicular lymphoma, or mantle cell lymphoma. Patients with a failed prior allogeneic stem cell transplant or secondary central nervous system involvement were eligible, but all patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
As the trial moved to the core pivotal phase, eligibility requirements shifted slightly to include patients with ECOG status 0 or 1, and lymphoma diagnoses narrowed to include only DLBCL not otherwise specified (NOS), transformed follicular lymphoma, and high-grade B-cell lymphoma with double- and triple-hit cytogenetics. The core group was nearing completion of accrual at the time of the presentation, which presented preliminary results from this phase of the trial.
Among the 88 evaluable patients in the initial population with DLBCL receiving any of three dose levels, the best overall response rate (ORR) was 74% (95% confidence interval, 63%-83%); 52% of these patients achieved complete response (CR; 95% CI, 41%-63%).
For patients receiving the higher dose of liso-cel, the ORR was 81% (95% CI, 62%-94%), with a 63% CR rate (95% CI, 42%-81%), bearing out the dose-response rate that had been seen earlier in the trial, Dr. Abramson said.
The median duration of response in all TRANSCEND patients was 9.2 months; the median duration of remission has not been reached, he said. “We see evidence of durable response at 3 months in all our high-risk subsets, and that includes double- and triple-hit lymphomas, double-expresser lymphomas, patients who’ve never achieved prior complete remission, and patients with refractory disease.”
“The overall results are similarly encouraging,” Dr. Abramson said, with 86% of all patients alive at 6 months. Among the complete responders, 94% are alive at the 6-month mark. “The median duration of complete responders has not been reached in this cohort,” he said.
These results are notable, Dr. Abramson said, since about 90% of study participants have at least one disease risk factor that would predict median overall survival of 3-6 months.
During the period after leukapheresis while the CAR T cells were in production, patients could have ongoing treatment, but received PET scans to confirm disease before continuing enrollment in the trial and receiving liso-cel. The time from apheresis to product release for the pivotal cohort is now under 21 days, he said.
The study was supported by Juno Therapeutics, which plans to market liso-cel. Dr. Abramson reported ties with Celgene, Gilead, Seattle Genetics, Novartis, and Genentech.
SOURCE: Abramson J et al. Abstract 5.
SALT LAKE CITY – A CD19-directed 4-1BB chimeric antigen receptor (CAR) T cell product showed efficacy and a low rate of cytokine release syndrome and neurotoxicity in patients with aggressive lymphomas and poor prognoses, raising the possibility of outpatient administration and fewer hospitalization days in this high-risk group.
A total of 86 patients who received inpatient infusions of lisocabtagene maraleucel (liso-cel, also known as JCAR017) had a mean 15.6 days of hospitalization, compared with 9.3 days for 8 outpatient recipients, said Jeremy Abramson, MD, speaking at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
As of October 2017, eight patients had received liso-cel infusion as outpatients with at least 28 days of postinfusion data, Dr. Abramson said.
Although all but one required hospital admission, at a median of 5 days postinfusion (range, 4-22 days), there had been no intensive care unit admissions, and no outpatient recipients had experienced severe cytokine release syndrome (CRS) or neurotoxicity. All admitted patients presented with fever.
Among the study population, “Cytokine release syndrome was only seen in 35% of our entire dataset,” with neurologic toxicity seen in 19% of participants, Dr. Abramson said. “The majority of subjects had no CRS and no toxicity,” he said. Severe CRS occurred in 1% of the study population, and severe neurotoxicity in 12%. There were no deaths related to either complication.
Dr. Abramson reported these results from the TRANSCEND NHL 001 trial, a seamless design phase 1 pivotal trial of liso-cel enrolling patients with relapsed and refractory aggressive B cell non-Hodgkin lymphoma (NHL). Liso-cel delivers CD19-directed CD4 and CD8 CAR T cells in a 1:1 ratio, said Dr. Abramson, director of the lymphoma program at the Massachusetts General Hospital Cancer Center, Boston.
A total of 91 patients were randomized to one of the three dose-finding cohorts of the multicenter trial of liso-cel. One cohort received 5 x 107 cells in a single dose; a second cohort received the same number of cells but in two doses administered 14 days apart; the third cohort received a single dose of 1 x 108 cells.
The seamless trial design then moved to dose expansion, using the two single doses established in the dose-finding phase of the study. Ultimately, Dr. Abramson said, the third and pivotal diffuse large B-cell lymphoma (DLBCL) cohort received the higher single dose, since a dose-response relationship was seen in the earlier cohorts. No increase in cytokine release syndrome or neurotoxicity has been seen with the higher dose in patients evaluated to date.
Patients (median age, 61 years) were eligible to participate in the trial if they had relapsed or refractory DLBCL, primary mediastinal B-cell lymphoma, grade 3B follicular lymphoma, or mantle cell lymphoma. Patients with a failed prior allogeneic stem cell transplant or secondary central nervous system involvement were eligible, but all patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
As the trial moved to the core pivotal phase, eligibility requirements shifted slightly to include patients with ECOG status 0 or 1, and lymphoma diagnoses narrowed to include only DLBCL not otherwise specified (NOS), transformed follicular lymphoma, and high-grade B-cell lymphoma with double- and triple-hit cytogenetics. The core group was nearing completion of accrual at the time of the presentation, which presented preliminary results from this phase of the trial.
Among the 88 evaluable patients in the initial population with DLBCL receiving any of three dose levels, the best overall response rate (ORR) was 74% (95% confidence interval, 63%-83%); 52% of these patients achieved complete response (CR; 95% CI, 41%-63%).
For patients receiving the higher dose of liso-cel, the ORR was 81% (95% CI, 62%-94%), with a 63% CR rate (95% CI, 42%-81%), bearing out the dose-response rate that had been seen earlier in the trial, Dr. Abramson said.
The median duration of response in all TRANSCEND patients was 9.2 months; the median duration of remission has not been reached, he said. “We see evidence of durable response at 3 months in all our high-risk subsets, and that includes double- and triple-hit lymphomas, double-expresser lymphomas, patients who’ve never achieved prior complete remission, and patients with refractory disease.”
“The overall results are similarly encouraging,” Dr. Abramson said, with 86% of all patients alive at 6 months. Among the complete responders, 94% are alive at the 6-month mark. “The median duration of complete responders has not been reached in this cohort,” he said.
These results are notable, Dr. Abramson said, since about 90% of study participants have at least one disease risk factor that would predict median overall survival of 3-6 months.
During the period after leukapheresis while the CAR T cells were in production, patients could have ongoing treatment, but received PET scans to confirm disease before continuing enrollment in the trial and receiving liso-cel. The time from apheresis to product release for the pivotal cohort is now under 21 days, he said.
The study was supported by Juno Therapeutics, which plans to market liso-cel. Dr. Abramson reported ties with Celgene, Gilead, Seattle Genetics, Novartis, and Genentech.
SOURCE: Abramson J et al. Abstract 5.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: High-risk lymphoma patients had more than 6 fewer inpatient days with outpatient CAR T infusion.
Study details: Seamless phase 1 trial initially evaluating 91 patients with relapsed/refractory diffuse large B cell lymphoma.
Disclosures: Juno Therapeutics sponsored the study. Dr. Abramson reported ties with Celgene, Gilead, Seattle Genetics, Novartis, and Genentech.
Source: Abramson J et al. Abstract 5.
Ibrutinib linked to invasive fungal infections
The tyrosine kinase inhibitor ibrutinib (Imbruvica) may be associated with early-onset invasive fungal infections (IFI) in patients with hematologic malignancies, investigators caution.
French investigators identified 33 cases of invasive fungal infections occurring among patients who had been treated with ibrutinib as monotherapy or in combination with other agents. Of the 33 cases, 27 were invasive aspergillosis, and 40% of these were localized in the central nervous system. The findings were published in the journal Blood.
“IFI tend to occur within the first months of treatment and are infrequent thereafter. Whilst it seems difficult at this point to advocate for systematic antifungal prophylaxis in all patients, an increased awareness about the potential risk of IFI after initiating ibrutinib is warranted, especially when other predisposing factors are associated,” wrote David Ghez, MD, PhD, and colleagues at the Gustave Roussy Institute in Villejuif and other centers in France.
Although ibrutinib, an inhibitor of Bruton’s tyrosine kinase, is generally considered to be less immunosuppressive than other therapies, it was associated with five cases of Pneumocystis jirovecii pneumonia in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib monotherapy in a 2016 report (Blood. 2016;128:1940-3). Of these five patients, four were treatment naive, suggesting that ibrutinib itself could increase risk for invasive opportunistic infections, Dr. Ghez and his colleagues noted.
Based on this finding and on case reports of invasive infections in other patients being treated with ibrutinib, the authors conducted a retrospective survey of centers in the French Innovative Leukemia Organization CLL group.
They identified 33 cases, including 30 patients with CLL (15 of whom had deleterious 17p deletions), 1 with mantle cell lymphoma, and 2 with Waldenstrom macroglobulinemia.
Invasive aspergillosis accounted for 27 of the 33 cases, and 11 cases had CNS localization. There were four cases of disseminated cryptococcosis, and one each of mucormycosis and pneumocystis pneumonia.
The median time between the start of ibrutinib therapy and a diagnosis of invasive fungal infection was 3 months, with some cases occurring as early as 1 month, and others occurring 30 months out. However, the majority of cases – 28 – were diagnosed within 6 months of the start of therapy, including 20 that occurred within 3 months of ibrutinib initiation.
In 21 patients, the diagnosis of an invasive fungal infection led to drug discontinuation. In the remaining patients, the drug was either resumed after resolution of the IFI, or continued at a lower dose because of potential for interaction between ibrutinib and the antifungal agent voriconazole.
Dr. Ghez reported receiving a research grant from Janssen, and coauthor Loic Ysebaert, MD, PhD, reported consultancy fees from the company. All other authors declared no competing financial interests.
hematologynews@frontlinemedcom.com
SOURCE: Ghez D et al., Blood. 2018 Feb 1. doi: 10.1182/blood-2017-11-818286.
The tyrosine kinase inhibitor ibrutinib (Imbruvica) may be associated with early-onset invasive fungal infections (IFI) in patients with hematologic malignancies, investigators caution.
French investigators identified 33 cases of invasive fungal infections occurring among patients who had been treated with ibrutinib as monotherapy or in combination with other agents. Of the 33 cases, 27 were invasive aspergillosis, and 40% of these were localized in the central nervous system. The findings were published in the journal Blood.
“IFI tend to occur within the first months of treatment and are infrequent thereafter. Whilst it seems difficult at this point to advocate for systematic antifungal prophylaxis in all patients, an increased awareness about the potential risk of IFI after initiating ibrutinib is warranted, especially when other predisposing factors are associated,” wrote David Ghez, MD, PhD, and colleagues at the Gustave Roussy Institute in Villejuif and other centers in France.
Although ibrutinib, an inhibitor of Bruton’s tyrosine kinase, is generally considered to be less immunosuppressive than other therapies, it was associated with five cases of Pneumocystis jirovecii pneumonia in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib monotherapy in a 2016 report (Blood. 2016;128:1940-3). Of these five patients, four were treatment naive, suggesting that ibrutinib itself could increase risk for invasive opportunistic infections, Dr. Ghez and his colleagues noted.
Based on this finding and on case reports of invasive infections in other patients being treated with ibrutinib, the authors conducted a retrospective survey of centers in the French Innovative Leukemia Organization CLL group.
They identified 33 cases, including 30 patients with CLL (15 of whom had deleterious 17p deletions), 1 with mantle cell lymphoma, and 2 with Waldenstrom macroglobulinemia.
Invasive aspergillosis accounted for 27 of the 33 cases, and 11 cases had CNS localization. There were four cases of disseminated cryptococcosis, and one each of mucormycosis and pneumocystis pneumonia.
The median time between the start of ibrutinib therapy and a diagnosis of invasive fungal infection was 3 months, with some cases occurring as early as 1 month, and others occurring 30 months out. However, the majority of cases – 28 – were diagnosed within 6 months of the start of therapy, including 20 that occurred within 3 months of ibrutinib initiation.
In 21 patients, the diagnosis of an invasive fungal infection led to drug discontinuation. In the remaining patients, the drug was either resumed after resolution of the IFI, or continued at a lower dose because of potential for interaction between ibrutinib and the antifungal agent voriconazole.
Dr. Ghez reported receiving a research grant from Janssen, and coauthor Loic Ysebaert, MD, PhD, reported consultancy fees from the company. All other authors declared no competing financial interests.
hematologynews@frontlinemedcom.com
SOURCE: Ghez D et al., Blood. 2018 Feb 1. doi: 10.1182/blood-2017-11-818286.
The tyrosine kinase inhibitor ibrutinib (Imbruvica) may be associated with early-onset invasive fungal infections (IFI) in patients with hematologic malignancies, investigators caution.
French investigators identified 33 cases of invasive fungal infections occurring among patients who had been treated with ibrutinib as monotherapy or in combination with other agents. Of the 33 cases, 27 were invasive aspergillosis, and 40% of these were localized in the central nervous system. The findings were published in the journal Blood.
“IFI tend to occur within the first months of treatment and are infrequent thereafter. Whilst it seems difficult at this point to advocate for systematic antifungal prophylaxis in all patients, an increased awareness about the potential risk of IFI after initiating ibrutinib is warranted, especially when other predisposing factors are associated,” wrote David Ghez, MD, PhD, and colleagues at the Gustave Roussy Institute in Villejuif and other centers in France.
Although ibrutinib, an inhibitor of Bruton’s tyrosine kinase, is generally considered to be less immunosuppressive than other therapies, it was associated with five cases of Pneumocystis jirovecii pneumonia in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib monotherapy in a 2016 report (Blood. 2016;128:1940-3). Of these five patients, four were treatment naive, suggesting that ibrutinib itself could increase risk for invasive opportunistic infections, Dr. Ghez and his colleagues noted.
Based on this finding and on case reports of invasive infections in other patients being treated with ibrutinib, the authors conducted a retrospective survey of centers in the French Innovative Leukemia Organization CLL group.
They identified 33 cases, including 30 patients with CLL (15 of whom had deleterious 17p deletions), 1 with mantle cell lymphoma, and 2 with Waldenstrom macroglobulinemia.
Invasive aspergillosis accounted for 27 of the 33 cases, and 11 cases had CNS localization. There were four cases of disseminated cryptococcosis, and one each of mucormycosis and pneumocystis pneumonia.
The median time between the start of ibrutinib therapy and a diagnosis of invasive fungal infection was 3 months, with some cases occurring as early as 1 month, and others occurring 30 months out. However, the majority of cases – 28 – were diagnosed within 6 months of the start of therapy, including 20 that occurred within 3 months of ibrutinib initiation.
In 21 patients, the diagnosis of an invasive fungal infection led to drug discontinuation. In the remaining patients, the drug was either resumed after resolution of the IFI, or continued at a lower dose because of potential for interaction between ibrutinib and the antifungal agent voriconazole.
Dr. Ghez reported receiving a research grant from Janssen, and coauthor Loic Ysebaert, MD, PhD, reported consultancy fees from the company. All other authors declared no competing financial interests.
hematologynews@frontlinemedcom.com
SOURCE: Ghez D et al., Blood. 2018 Feb 1. doi: 10.1182/blood-2017-11-818286.
FROM BLOOD
Key clinical point:
Major finding: Of 33 identified cases, 27 were invasive aspergillosis.
Study details: Retrospective review of case reports from 16 French centers.
Disclosures: Dr. Ghez reported receiving a research grant from Janssen, and coauthor Loic Ysebaert, MD, PhD, reported consultancy fees with the company. All other authors declared no competing financial interests.
Source: Ghez D et al. Blood. 2018 Feb 1. doi: 10.1182/blood-2017-11-818286.
Acalabrutinib shows less off-target activity in mantle cell lymphoma
A new Bruton tyrosine kinase inhibitor has shown a high response rate and favorable safety profile in the treatment of patients with mantle cell lymphoma.
Researchers reported the results of an open-label, phase 2 study of oral acalabrutinib (100 mg, twice daily) in 124 patients with relapsed or refractory mantle cell lymphoma in The Lancet. Acalabrutinib (Calquence) received accelerated approval from the Food and Drug Administration in October 2017 for treatment of adults with mantle cell lymphoma who have received at least one prior therapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica), which was approved in 2013 for the treatment of mantle cell lymphoma, has been associated with side effects including atrial fibrillation, infections and bleeding, likely due to its off-target activity against other kinases. But acalabrutinib (ACP-196) “is a highly selective, potent BTK inhibitor developed to minimise off-target activity,” wrote Michael Wang, MD, of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
After a median follow-up of 15.2 months, 81% of patients in the study achieved an investigator-assessed overall response based on Lugano classification, with 40% achieving a complete response. The results were similar according to an independent review committee evaluation of responses based on CT and PET scans, bone-marrow biopsy specimens, endoscopy results, and clinical data.
There was also a reduction in lymphadenopathy seen in 94% of patients. The patients who showed a complete response took a median of 3.4 months to get there, and the median time to best response was 1.9 months.
The researchers also looked at response rates across a number of prespecified subgroups. Patients with Ann Arbor stage IV disease, those with bone marrow involvement, and those with extranodal disease were less likely to achieve a complete response (29%, 14% and 28% respectively). Patients with lymph nodes 5 cm or larger in diameter showed a 78% response rate.
While the Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached, 87% of patients achieved 12-month overall survival and 67% of patients achieved progression-free survival at 12 months.
Most of the adverse events were grade 1 or 2, and included headache, diarrhea, fatigue, and myalgia.
There were no grade 4 or 5 adverse events, but 10% of patients experienced neutropenia, 9% experienced anemia and 5% experienced pneumonia. There was also one case of grade 3 or worse hemorrhage, but no cases of atrial fibrillation. Lymphocytosis was seen in 31% of patients.
Nearly half of patients (44%) discontinued treatment, mostly because of progressive disease (31%) but 6% discontinued the treatment because of adverse events.
“Overall, treatment with acalabrutinib demonstrated a favourable benefit-risk profile and represents a promising treatment option for patients with relapsed or refractory mantle cell lymphoma,” the researchers wrote. “Data from the ongoing ACE-CL-006 trial directly comparing acalabrutinib with ibrutinib in previously treated patients with high-risk chronic lymphocytic leukaemia will further differentiate the safety profiles of the two treatments.”
The researchers noted a decrease in plasma levels of tumor necrosis factor alpha, the cytokine CXCL13, and other cytokines known to be involved in inflammation and cell trafficking.
“These findings add to the growing body of evidence indicating that BTK inhibition disrupts the tumour microenvironment, limiting the supply of cytokines and chemokines necessary for complex interactions with stromal and accessory cells important for tumour growth and survival.”
The study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. Several study authors reported grants, personal fees and other support from the pharmaceutical industry, including Acerta Pharma, most outside the submitted work. Several authors were also employees of Acerta and some had acalabrutinib patents pending or issued.
hematologynews@frontlinemedcom.com
SOURCE: Wang M et al., Lancet. 2018;391:659-67.
A new Bruton tyrosine kinase inhibitor has shown a high response rate and favorable safety profile in the treatment of patients with mantle cell lymphoma.
Researchers reported the results of an open-label, phase 2 study of oral acalabrutinib (100 mg, twice daily) in 124 patients with relapsed or refractory mantle cell lymphoma in The Lancet. Acalabrutinib (Calquence) received accelerated approval from the Food and Drug Administration in October 2017 for treatment of adults with mantle cell lymphoma who have received at least one prior therapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica), which was approved in 2013 for the treatment of mantle cell lymphoma, has been associated with side effects including atrial fibrillation, infections and bleeding, likely due to its off-target activity against other kinases. But acalabrutinib (ACP-196) “is a highly selective, potent BTK inhibitor developed to minimise off-target activity,” wrote Michael Wang, MD, of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
After a median follow-up of 15.2 months, 81% of patients in the study achieved an investigator-assessed overall response based on Lugano classification, with 40% achieving a complete response. The results were similar according to an independent review committee evaluation of responses based on CT and PET scans, bone-marrow biopsy specimens, endoscopy results, and clinical data.
There was also a reduction in lymphadenopathy seen in 94% of patients. The patients who showed a complete response took a median of 3.4 months to get there, and the median time to best response was 1.9 months.
The researchers also looked at response rates across a number of prespecified subgroups. Patients with Ann Arbor stage IV disease, those with bone marrow involvement, and those with extranodal disease were less likely to achieve a complete response (29%, 14% and 28% respectively). Patients with lymph nodes 5 cm or larger in diameter showed a 78% response rate.
While the Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached, 87% of patients achieved 12-month overall survival and 67% of patients achieved progression-free survival at 12 months.
Most of the adverse events were grade 1 or 2, and included headache, diarrhea, fatigue, and myalgia.
There were no grade 4 or 5 adverse events, but 10% of patients experienced neutropenia, 9% experienced anemia and 5% experienced pneumonia. There was also one case of grade 3 or worse hemorrhage, but no cases of atrial fibrillation. Lymphocytosis was seen in 31% of patients.
Nearly half of patients (44%) discontinued treatment, mostly because of progressive disease (31%) but 6% discontinued the treatment because of adverse events.
“Overall, treatment with acalabrutinib demonstrated a favourable benefit-risk profile and represents a promising treatment option for patients with relapsed or refractory mantle cell lymphoma,” the researchers wrote. “Data from the ongoing ACE-CL-006 trial directly comparing acalabrutinib with ibrutinib in previously treated patients with high-risk chronic lymphocytic leukaemia will further differentiate the safety profiles of the two treatments.”
The researchers noted a decrease in plasma levels of tumor necrosis factor alpha, the cytokine CXCL13, and other cytokines known to be involved in inflammation and cell trafficking.
“These findings add to the growing body of evidence indicating that BTK inhibition disrupts the tumour microenvironment, limiting the supply of cytokines and chemokines necessary for complex interactions with stromal and accessory cells important for tumour growth and survival.”
The study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. Several study authors reported grants, personal fees and other support from the pharmaceutical industry, including Acerta Pharma, most outside the submitted work. Several authors were also employees of Acerta and some had acalabrutinib patents pending or issued.
hematologynews@frontlinemedcom.com
SOURCE: Wang M et al., Lancet. 2018;391:659-67.
A new Bruton tyrosine kinase inhibitor has shown a high response rate and favorable safety profile in the treatment of patients with mantle cell lymphoma.
Researchers reported the results of an open-label, phase 2 study of oral acalabrutinib (100 mg, twice daily) in 124 patients with relapsed or refractory mantle cell lymphoma in The Lancet. Acalabrutinib (Calquence) received accelerated approval from the Food and Drug Administration in October 2017 for treatment of adults with mantle cell lymphoma who have received at least one prior therapy.
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica), which was approved in 2013 for the treatment of mantle cell lymphoma, has been associated with side effects including atrial fibrillation, infections and bleeding, likely due to its off-target activity against other kinases. But acalabrutinib (ACP-196) “is a highly selective, potent BTK inhibitor developed to minimise off-target activity,” wrote Michael Wang, MD, of the department of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.
After a median follow-up of 15.2 months, 81% of patients in the study achieved an investigator-assessed overall response based on Lugano classification, with 40% achieving a complete response. The results were similar according to an independent review committee evaluation of responses based on CT and PET scans, bone-marrow biopsy specimens, endoscopy results, and clinical data.
There was also a reduction in lymphadenopathy seen in 94% of patients. The patients who showed a complete response took a median of 3.4 months to get there, and the median time to best response was 1.9 months.
The researchers also looked at response rates across a number of prespecified subgroups. Patients with Ann Arbor stage IV disease, those with bone marrow involvement, and those with extranodal disease were less likely to achieve a complete response (29%, 14% and 28% respectively). Patients with lymph nodes 5 cm or larger in diameter showed a 78% response rate.
While the Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached, 87% of patients achieved 12-month overall survival and 67% of patients achieved progression-free survival at 12 months.
Most of the adverse events were grade 1 or 2, and included headache, diarrhea, fatigue, and myalgia.
There were no grade 4 or 5 adverse events, but 10% of patients experienced neutropenia, 9% experienced anemia and 5% experienced pneumonia. There was also one case of grade 3 or worse hemorrhage, but no cases of atrial fibrillation. Lymphocytosis was seen in 31% of patients.
Nearly half of patients (44%) discontinued treatment, mostly because of progressive disease (31%) but 6% discontinued the treatment because of adverse events.
“Overall, treatment with acalabrutinib demonstrated a favourable benefit-risk profile and represents a promising treatment option for patients with relapsed or refractory mantle cell lymphoma,” the researchers wrote. “Data from the ongoing ACE-CL-006 trial directly comparing acalabrutinib with ibrutinib in previously treated patients with high-risk chronic lymphocytic leukaemia will further differentiate the safety profiles of the two treatments.”
The researchers noted a decrease in plasma levels of tumor necrosis factor alpha, the cytokine CXCL13, and other cytokines known to be involved in inflammation and cell trafficking.
“These findings add to the growing body of evidence indicating that BTK inhibition disrupts the tumour microenvironment, limiting the supply of cytokines and chemokines necessary for complex interactions with stromal and accessory cells important for tumour growth and survival.”
The study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. Several study authors reported grants, personal fees and other support from the pharmaceutical industry, including Acerta Pharma, most outside the submitted work. Several authors were also employees of Acerta and some had acalabrutinib patents pending or issued.
hematologynews@frontlinemedcom.com
SOURCE: Wang M et al., Lancet. 2018;391:659-67.
FROM THE LANCET
Key clinical point:
Major finding: Eighty-one percent of patients with relapsed or refractory mantle cell lymphoma showed a partial or complete response to Bruton tyrosine kinase inhibitor acalabrutinib.
Study details: An open-label, phase 2 study in 124 patients with relapsed or refractory mantle cell lymphoma.
Disclosures: The study was sponsored by Acerta Pharma, a member of the AstraZeneca Group. Several study authors reported grants, personal fees and other support from the pharmaceutical industry, including Acerta Pharma, most outside the submitted work. Several authors were also employees of Acerta and some had acalabrutinib patents pending or issued.
Source: Wang M et al. Lancet. 2018;391:659-67.
NF-kappaB pathway could help solve resistance problem in mantle cell lymphoma
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
B-cell receptor (BCR) resistance is a significant treatment obstacle in mantle cell lymphoma (MCL), but a new study highlights the potential protective role for cells expressing specific ligands.
Hilka Rauert-Wunderlich, of the University of Würzburg and Comprehensive Cancer Center, Germany, and her colleagues stimulated the REC-1, MAVER-1, and L-929 cell lines to show the role of the alternative nuclear factor-kappa B (NF-kappaB) pathway and the tumor necrosis factor ligand CD40L.
Viability assays showed a protective effect of CD40L prestimulation on BCR inhibitor treatment. The effect was detectable and significant in the REC-1 cell line for both ibrutinib and sotrastaurin at “clinically relevant concentrations” and in the resistant MAVER-1 cell line at “nonphysiologically high” sotrastaurin concentrations. CD40L stimulation also induced alternative NF-kappaB pathway signaling in both REC-1 and MAVER-1 cell lines.
“The data presented in this study argue for the protective potential of microenvironmentally mediated activation of the alternative [NF-kappaB] pathway in MCL cell against BCR signaling-associated drugs, which might represent a physiologic niche for MCL relapse. Additionally, these data provide evidence for the potential of the alternative [NF-kappaB] pathway as a possible therapeutic target in MCL,” the researchers wrote in Cell Death & Disease.
The researchers reported having no conflicts of interest.
SOURCE: Rauert-Wunderlich H et al. Cell Death Dis. 2018 Jan 24. doi: 10.1038/s41419-017-0157-6.
FROM CELL DEATH & DISEASE