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FDA approves rituximab biosimilar for lymphoma
(NHL).
Celltrion’s Truxima (rituximab-abbs) is a biosimilar of Genentech’s Rituxan (rituximab) and the first biosimilar approved in the United States to treat NHL.
Truxima (formerly CT-P10) is approved to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy. Truxima is approved as a single agent to treat relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL. Truxima is approved in combination with first-line chemotherapy to treat previously untreated follicular, CD20-positive, B-cell NHL.
Truxima is approved as single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response to a rituximab product in combination with chemotherapy. Truxima also is approved as a single agent to treat nonprogressing, low-grade, CD20-positive, B-cell NHL after first-line treatment with cyclophosphamide, vincristine, and prednisone.The label for Truxima contains a boxed warning detailing the risk of fatal infusion reactions, severe skin and mouth reactions (some with fatal outcomes), hepatitis B virus reactivation that may cause serious liver problems (including liver failure and death), and progressive multifocal leukoencephalopathy.
The FDA said its approval of Truxima is “based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrates Truxima is biosimilar to Rituxan.”
Findings from a phase 3 trial suggested that Truxima is equivalent to the reference product in patients with low-tumor-burden follicular lymphoma (Lancet Haematol. 2018 Nov;5[11]:e543-53).
(NHL).
Celltrion’s Truxima (rituximab-abbs) is a biosimilar of Genentech’s Rituxan (rituximab) and the first biosimilar approved in the United States to treat NHL.
Truxima (formerly CT-P10) is approved to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy. Truxima is approved as a single agent to treat relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL. Truxima is approved in combination with first-line chemotherapy to treat previously untreated follicular, CD20-positive, B-cell NHL.
Truxima is approved as single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response to a rituximab product in combination with chemotherapy. Truxima also is approved as a single agent to treat nonprogressing, low-grade, CD20-positive, B-cell NHL after first-line treatment with cyclophosphamide, vincristine, and prednisone.The label for Truxima contains a boxed warning detailing the risk of fatal infusion reactions, severe skin and mouth reactions (some with fatal outcomes), hepatitis B virus reactivation that may cause serious liver problems (including liver failure and death), and progressive multifocal leukoencephalopathy.
The FDA said its approval of Truxima is “based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrates Truxima is biosimilar to Rituxan.”
Findings from a phase 3 trial suggested that Truxima is equivalent to the reference product in patients with low-tumor-burden follicular lymphoma (Lancet Haematol. 2018 Nov;5[11]:e543-53).
(NHL).
Celltrion’s Truxima (rituximab-abbs) is a biosimilar of Genentech’s Rituxan (rituximab) and the first biosimilar approved in the United States to treat NHL.
Truxima (formerly CT-P10) is approved to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy. Truxima is approved as a single agent to treat relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL. Truxima is approved in combination with first-line chemotherapy to treat previously untreated follicular, CD20-positive, B-cell NHL.
Truxima is approved as single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response to a rituximab product in combination with chemotherapy. Truxima also is approved as a single agent to treat nonprogressing, low-grade, CD20-positive, B-cell NHL after first-line treatment with cyclophosphamide, vincristine, and prednisone.The label for Truxima contains a boxed warning detailing the risk of fatal infusion reactions, severe skin and mouth reactions (some with fatal outcomes), hepatitis B virus reactivation that may cause serious liver problems (including liver failure and death), and progressive multifocal leukoencephalopathy.
The FDA said its approval of Truxima is “based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrates Truxima is biosimilar to Rituxan.”
Findings from a phase 3 trial suggested that Truxima is equivalent to the reference product in patients with low-tumor-burden follicular lymphoma (Lancet Haematol. 2018 Nov;5[11]:e543-53).
FDA expands approval of brentuximab vedotin to PTCL
The , marking the first FDA approval of a treatment for newly-diagnosed PTCL.
The drug, which is marketed by Seattle Genetics as Adcetris, is a monoclonal antibody that binds to CD30 protein found on some cancer cells.
It was previously approved for adult patients with untreated stage III or IV classical Hodgkin lymphoma (cHL), cHL after relapse, cHL after stem cell transplant in patients at high risk for relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after other treatments fail, and primary cutaneous ALCL or CD30-expressing mycosis fungoides after other treatments fail.
The expanded approval, which followed the granting of Priority Review and Breakthrough Therapy designations for the supplemental Biologic License Application, was made using the FDA’s new Real-Time Oncology Review pilot program (RTOR). This program allows for data review and communication with a sponsor prior to official application submission with the goal of speeding up the review process.
The brentuximab vedotin approval now extends to previously untreated systemic ALCL and other CD30-expressing PTCLs in combination with chemotherapy.
Approval was based on the ECHELON-2 clinical trial involving 452 patients, which demonstrated improved progression-free survival (PFS) in patients with certain types of PTCL who were treated first-line with either brentuximab vedotin plus chemotherapy with cyclophosphamide, doxorubicin, prednisone (CHP), or standard chemotherapy with CHP and vincristine (CHOP). Median PFS was 48 months vs. 21 months in the groups, respectively (hazard ratio, 0.71).
The FDA advises health care providers to “monitor patients for infusion reactions, life-threatening allergic reactions (anaphylaxis), neuropathy, fever, gastrointestinal complications, and infections,” according to a press release announcing the approval, which also states that patients should be monitored for tumor lysis syndrome, serious skin reactions, pulmonary toxicity, and hepatotoxicity.
The drug may cause harm to a developing fetus or newborn and should not be used in women who are pregnant or breastfeeding. A Boxed Warning regarding risk of progressive multifocal leukoencephalopathy is also included in the prescribing information.
The current standard of care for initial treatment of PTCL is multiagent chemotherapy – a treatment that “has not significantly changed in decades and is too often unsuccessful in leading to long-term remissions, underscoring the need for new treatments, ” Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York, said in a statement issued by Seattle Genetics.
“With this approval, clinicians have the opportunity to transform the way newly diagnosed CD30-expressing PTCL patients are treated,” Dr. Horwitz said.
The ECHELON-2 data will be presented at the American Society of Hematology annual meeting in San Diego on Monday, Dec. 3, 2018.
The , marking the first FDA approval of a treatment for newly-diagnosed PTCL.
The drug, which is marketed by Seattle Genetics as Adcetris, is a monoclonal antibody that binds to CD30 protein found on some cancer cells.
It was previously approved for adult patients with untreated stage III or IV classical Hodgkin lymphoma (cHL), cHL after relapse, cHL after stem cell transplant in patients at high risk for relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after other treatments fail, and primary cutaneous ALCL or CD30-expressing mycosis fungoides after other treatments fail.
The expanded approval, which followed the granting of Priority Review and Breakthrough Therapy designations for the supplemental Biologic License Application, was made using the FDA’s new Real-Time Oncology Review pilot program (RTOR). This program allows for data review and communication with a sponsor prior to official application submission with the goal of speeding up the review process.
The brentuximab vedotin approval now extends to previously untreated systemic ALCL and other CD30-expressing PTCLs in combination with chemotherapy.
Approval was based on the ECHELON-2 clinical trial involving 452 patients, which demonstrated improved progression-free survival (PFS) in patients with certain types of PTCL who were treated first-line with either brentuximab vedotin plus chemotherapy with cyclophosphamide, doxorubicin, prednisone (CHP), or standard chemotherapy with CHP and vincristine (CHOP). Median PFS was 48 months vs. 21 months in the groups, respectively (hazard ratio, 0.71).
The FDA advises health care providers to “monitor patients for infusion reactions, life-threatening allergic reactions (anaphylaxis), neuropathy, fever, gastrointestinal complications, and infections,” according to a press release announcing the approval, which also states that patients should be monitored for tumor lysis syndrome, serious skin reactions, pulmonary toxicity, and hepatotoxicity.
The drug may cause harm to a developing fetus or newborn and should not be used in women who are pregnant or breastfeeding. A Boxed Warning regarding risk of progressive multifocal leukoencephalopathy is also included in the prescribing information.
The current standard of care for initial treatment of PTCL is multiagent chemotherapy – a treatment that “has not significantly changed in decades and is too often unsuccessful in leading to long-term remissions, underscoring the need for new treatments, ” Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York, said in a statement issued by Seattle Genetics.
“With this approval, clinicians have the opportunity to transform the way newly diagnosed CD30-expressing PTCL patients are treated,” Dr. Horwitz said.
The ECHELON-2 data will be presented at the American Society of Hematology annual meeting in San Diego on Monday, Dec. 3, 2018.
The , marking the first FDA approval of a treatment for newly-diagnosed PTCL.
The drug, which is marketed by Seattle Genetics as Adcetris, is a monoclonal antibody that binds to CD30 protein found on some cancer cells.
It was previously approved for adult patients with untreated stage III or IV classical Hodgkin lymphoma (cHL), cHL after relapse, cHL after stem cell transplant in patients at high risk for relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after other treatments fail, and primary cutaneous ALCL or CD30-expressing mycosis fungoides after other treatments fail.
The expanded approval, which followed the granting of Priority Review and Breakthrough Therapy designations for the supplemental Biologic License Application, was made using the FDA’s new Real-Time Oncology Review pilot program (RTOR). This program allows for data review and communication with a sponsor prior to official application submission with the goal of speeding up the review process.
The brentuximab vedotin approval now extends to previously untreated systemic ALCL and other CD30-expressing PTCLs in combination with chemotherapy.
Approval was based on the ECHELON-2 clinical trial involving 452 patients, which demonstrated improved progression-free survival (PFS) in patients with certain types of PTCL who were treated first-line with either brentuximab vedotin plus chemotherapy with cyclophosphamide, doxorubicin, prednisone (CHP), or standard chemotherapy with CHP and vincristine (CHOP). Median PFS was 48 months vs. 21 months in the groups, respectively (hazard ratio, 0.71).
The FDA advises health care providers to “monitor patients for infusion reactions, life-threatening allergic reactions (anaphylaxis), neuropathy, fever, gastrointestinal complications, and infections,” according to a press release announcing the approval, which also states that patients should be monitored for tumor lysis syndrome, serious skin reactions, pulmonary toxicity, and hepatotoxicity.
The drug may cause harm to a developing fetus or newborn and should not be used in women who are pregnant or breastfeeding. A Boxed Warning regarding risk of progressive multifocal leukoencephalopathy is also included in the prescribing information.
The current standard of care for initial treatment of PTCL is multiagent chemotherapy – a treatment that “has not significantly changed in decades and is too often unsuccessful in leading to long-term remissions, underscoring the need for new treatments, ” Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York, said in a statement issued by Seattle Genetics.
“With this approval, clinicians have the opportunity to transform the way newly diagnosed CD30-expressing PTCL patients are treated,” Dr. Horwitz said.
The ECHELON-2 data will be presented at the American Society of Hematology annual meeting in San Diego on Monday, Dec. 3, 2018.
Bortezomib may unlock resistance in WM with mutations
The use of bortezomib may help overcome treatment resistance in patients with Waldenström macroglobulinemia (WM) with CXCR4 mutations, according to new research.
Romanos Sklavenitis-Pistofidis, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues compared the effects of treatment with bortezomib/rituximab in patients with WM based on their CXCR4 mutation status. They found no significant difference in progression-free survival (Log-rank, P = .994) or overall survival (Log-rank, P = .407) when comparing patients who have CXCR4 mutations with those who have CXCR4 wild type.
“We report for the first time that a bortezomib-based combination is impervious to the impact of CXCR4 mutations in a cohort of patients with WM,” the researchers wrote in Blood. “Previously, we had shown this to be true in WM cell lines, whereby genetically engineering BCWM.1 and MWCL-1 to overexpress CXCR4 had no impact on bortezomib resistance.”
The researchers noted, however, that the mechanism at work may be different than that seen with bortezomib in other cancers.
“Different experiments have linked CXCR4 expression and bortezomib in a variety of ways in other hematological malignancies, including multiple myeloma. However, despite the complicated association in those cancer types, in WM there seems to be a consistently neutral effect of CXCR4 mutations on bortezomib resistance in both cell line and patient data,” they wrote.
The researchers recommended that the theory be tested in a prospective trial of bortezomib-based therapy in WM patients with CXCR4 mutations. Another question to be investigated, they pointed out, is the role of rituximab in the survival results seen in the current analysis.
The study included 63 patients with WM who were treated with bortezomib/rituximab either as upfront treatment or in the relapsed/refractory setting as part of a phase 2 trial.
Bortezomib was given by IV weekly at 1.6 mg/m2 for six cycles and rituximab was given at 375 mg/m2 during cycles one and four. Patients were taken off therapy after two cycles if they had progressive disease.
The researchers excluded 20 patients from the study because of a lack of material for genotyping. However, they noted that their clinical characteristics were not different from those patients who were included.
Out of 43 patients who were genotyped for CXCR4, 17 patients had a mutation. All patients who carried a CXCR4 mutation also had MYD88 L265P. Ten patients had frameshift mutations, one patient had a nonsense mutation, and six patients had missense mutations. The median follow-up of the analysis was 90.7 months.
The researchers repeated the analysis after excluding six patients with missense mutations and accounting for different treatment settings and found that survival remained unchanged.
The study was supported by the National Institutes of Health, the Leukemia and Lymphoma Society, and the International Waldenström Macroglobulinemia Foundation. One of the authors reported consulting and research funding from Takeda, which markets bortezomib, and other companies.
SOURCE: Sklavenitis-Pistofidis R et al. Blood. 2018 Oct 26. doi: 10.1182/blood-2018-07-863241.
The use of bortezomib may help overcome treatment resistance in patients with Waldenström macroglobulinemia (WM) with CXCR4 mutations, according to new research.
Romanos Sklavenitis-Pistofidis, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues compared the effects of treatment with bortezomib/rituximab in patients with WM based on their CXCR4 mutation status. They found no significant difference in progression-free survival (Log-rank, P = .994) or overall survival (Log-rank, P = .407) when comparing patients who have CXCR4 mutations with those who have CXCR4 wild type.
“We report for the first time that a bortezomib-based combination is impervious to the impact of CXCR4 mutations in a cohort of patients with WM,” the researchers wrote in Blood. “Previously, we had shown this to be true in WM cell lines, whereby genetically engineering BCWM.1 and MWCL-1 to overexpress CXCR4 had no impact on bortezomib resistance.”
The researchers noted, however, that the mechanism at work may be different than that seen with bortezomib in other cancers.
“Different experiments have linked CXCR4 expression and bortezomib in a variety of ways in other hematological malignancies, including multiple myeloma. However, despite the complicated association in those cancer types, in WM there seems to be a consistently neutral effect of CXCR4 mutations on bortezomib resistance in both cell line and patient data,” they wrote.
The researchers recommended that the theory be tested in a prospective trial of bortezomib-based therapy in WM patients with CXCR4 mutations. Another question to be investigated, they pointed out, is the role of rituximab in the survival results seen in the current analysis.
The study included 63 patients with WM who were treated with bortezomib/rituximab either as upfront treatment or in the relapsed/refractory setting as part of a phase 2 trial.
Bortezomib was given by IV weekly at 1.6 mg/m2 for six cycles and rituximab was given at 375 mg/m2 during cycles one and four. Patients were taken off therapy after two cycles if they had progressive disease.
The researchers excluded 20 patients from the study because of a lack of material for genotyping. However, they noted that their clinical characteristics were not different from those patients who were included.
Out of 43 patients who were genotyped for CXCR4, 17 patients had a mutation. All patients who carried a CXCR4 mutation also had MYD88 L265P. Ten patients had frameshift mutations, one patient had a nonsense mutation, and six patients had missense mutations. The median follow-up of the analysis was 90.7 months.
The researchers repeated the analysis after excluding six patients with missense mutations and accounting for different treatment settings and found that survival remained unchanged.
The study was supported by the National Institutes of Health, the Leukemia and Lymphoma Society, and the International Waldenström Macroglobulinemia Foundation. One of the authors reported consulting and research funding from Takeda, which markets bortezomib, and other companies.
SOURCE: Sklavenitis-Pistofidis R et al. Blood. 2018 Oct 26. doi: 10.1182/blood-2018-07-863241.
The use of bortezomib may help overcome treatment resistance in patients with Waldenström macroglobulinemia (WM) with CXCR4 mutations, according to new research.
Romanos Sklavenitis-Pistofidis, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues compared the effects of treatment with bortezomib/rituximab in patients with WM based on their CXCR4 mutation status. They found no significant difference in progression-free survival (Log-rank, P = .994) or overall survival (Log-rank, P = .407) when comparing patients who have CXCR4 mutations with those who have CXCR4 wild type.
“We report for the first time that a bortezomib-based combination is impervious to the impact of CXCR4 mutations in a cohort of patients with WM,” the researchers wrote in Blood. “Previously, we had shown this to be true in WM cell lines, whereby genetically engineering BCWM.1 and MWCL-1 to overexpress CXCR4 had no impact on bortezomib resistance.”
The researchers noted, however, that the mechanism at work may be different than that seen with bortezomib in other cancers.
“Different experiments have linked CXCR4 expression and bortezomib in a variety of ways in other hematological malignancies, including multiple myeloma. However, despite the complicated association in those cancer types, in WM there seems to be a consistently neutral effect of CXCR4 mutations on bortezomib resistance in both cell line and patient data,” they wrote.
The researchers recommended that the theory be tested in a prospective trial of bortezomib-based therapy in WM patients with CXCR4 mutations. Another question to be investigated, they pointed out, is the role of rituximab in the survival results seen in the current analysis.
The study included 63 patients with WM who were treated with bortezomib/rituximab either as upfront treatment or in the relapsed/refractory setting as part of a phase 2 trial.
Bortezomib was given by IV weekly at 1.6 mg/m2 for six cycles and rituximab was given at 375 mg/m2 during cycles one and four. Patients were taken off therapy after two cycles if they had progressive disease.
The researchers excluded 20 patients from the study because of a lack of material for genotyping. However, they noted that their clinical characteristics were not different from those patients who were included.
Out of 43 patients who were genotyped for CXCR4, 17 patients had a mutation. All patients who carried a CXCR4 mutation also had MYD88 L265P. Ten patients had frameshift mutations, one patient had a nonsense mutation, and six patients had missense mutations. The median follow-up of the analysis was 90.7 months.
The researchers repeated the analysis after excluding six patients with missense mutations and accounting for different treatment settings and found that survival remained unchanged.
The study was supported by the National Institutes of Health, the Leukemia and Lymphoma Society, and the International Waldenström Macroglobulinemia Foundation. One of the authors reported consulting and research funding from Takeda, which markets bortezomib, and other companies.
SOURCE: Sklavenitis-Pistofidis R et al. Blood. 2018 Oct 26. doi: 10.1182/blood-2018-07-863241.
FROM BLOOD
Key clinical point:
Major finding: Progression-free and overall survival were not significantly different between WM patients with CXCR4 mutations and those with CXCR4 wild type (log-rank, P = .994 and P = .407, respectively).
Study details: An analysis of 43 WM patients treated with bortezomib/rituximab and genotyped to determine CXCR4 mutation status.
Disclosures: The study was supported by the National Institutes of Health, the Leukemia and Lymphoma Society, and the International Waldenström Macroglobulinemia Foundation. One of the authors reported consulting and research funding from Takeda, which markets bortezomib, and other companies.
Source: Sklavenitis-Pistofidis R et al. Blood. 2018 Oct 26. doi: 10.1182/blood-2018-07-863241.
Azacitidine-nivolumab combo 'encouraging' in AML
The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.
The overall response rate was 33%, and the median overall survival (OS) was 6.3 months. However, the researchers identified factors associated with improved response and survival that could be used to select patients for this treatment.
A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment related.
Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported these results in Cancer Discovery.
The trial included 70 patients with a median age of 70 years. More than half of the patients (56%) had de novo AML, and 44% had secondary AML. The median number of prior therapies was two; 64% of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).
For this trial, patients received azacitidine at 75 mg/m2 on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was three. Patients had a median time on study of 3.5 months and reasons for discontinuation included primary refractory disease, relapse after initial response, proceeding to SCT, patient preference, and death.
The most common treatment-related, nonhematologic AEs were constipation, diarrhea, pneumonitis, nausea, and lung infection. The rate of immune-related AEs was 25% (n = 18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4); 14 responded to steroids and were safely rechallenged with nivolumab, according to the researchers.
Nine patients (13%) discontinued nivolumab (but continued with azacitidine) because of AEs. Two patients died of AEs that were considered possibly related to treatment. One death was caused by progressive pneumonia/pneumonitis, and one was caused by hemophagocytic lymphohistiocytosis.
The overall response rate was 33% (n = 23), with 4 patients achieving a complete response (CR) and 11 achieving a CR with incomplete count recovery (CRi). One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.
The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. Additionally, a higher frequency of pretherapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.
“In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” Dr. Daver said in a statement.
At a median follow-up of 21.4 months, 81% of patients (n = 57) had died; 16 died on study treatment and 41 died after discontinuation. The median OS overall was 6.3 months, and the median event-free survival was 4.5 months.
The median OS was 16.1 months in patients with CR/CRi, partial response, hematologic improvement, or stable disease and 4.1 months in nonresponders (P less than .0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P less than .001).
The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.
Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory AML.
“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Dr. Daver said.
This research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Individual researchers also reported financial relationships with Bristol-Myers Squibb.
SOURCE: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.
The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.
The overall response rate was 33%, and the median overall survival (OS) was 6.3 months. However, the researchers identified factors associated with improved response and survival that could be used to select patients for this treatment.
A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment related.
Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported these results in Cancer Discovery.
The trial included 70 patients with a median age of 70 years. More than half of the patients (56%) had de novo AML, and 44% had secondary AML. The median number of prior therapies was two; 64% of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).
For this trial, patients received azacitidine at 75 mg/m2 on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was three. Patients had a median time on study of 3.5 months and reasons for discontinuation included primary refractory disease, relapse after initial response, proceeding to SCT, patient preference, and death.
The most common treatment-related, nonhematologic AEs were constipation, diarrhea, pneumonitis, nausea, and lung infection. The rate of immune-related AEs was 25% (n = 18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4); 14 responded to steroids and were safely rechallenged with nivolumab, according to the researchers.
Nine patients (13%) discontinued nivolumab (but continued with azacitidine) because of AEs. Two patients died of AEs that were considered possibly related to treatment. One death was caused by progressive pneumonia/pneumonitis, and one was caused by hemophagocytic lymphohistiocytosis.
The overall response rate was 33% (n = 23), with 4 patients achieving a complete response (CR) and 11 achieving a CR with incomplete count recovery (CRi). One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.
The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. Additionally, a higher frequency of pretherapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.
“In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” Dr. Daver said in a statement.
At a median follow-up of 21.4 months, 81% of patients (n = 57) had died; 16 died on study treatment and 41 died after discontinuation. The median OS overall was 6.3 months, and the median event-free survival was 4.5 months.
The median OS was 16.1 months in patients with CR/CRi, partial response, hematologic improvement, or stable disease and 4.1 months in nonresponders (P less than .0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P less than .001).
The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.
Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory AML.
“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Dr. Daver said.
This research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Individual researchers also reported financial relationships with Bristol-Myers Squibb.
SOURCE: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.
The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.
The overall response rate was 33%, and the median overall survival (OS) was 6.3 months. However, the researchers identified factors associated with improved response and survival that could be used to select patients for this treatment.
A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment related.
Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported these results in Cancer Discovery.
The trial included 70 patients with a median age of 70 years. More than half of the patients (56%) had de novo AML, and 44% had secondary AML. The median number of prior therapies was two; 64% of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).
For this trial, patients received azacitidine at 75 mg/m2 on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was three. Patients had a median time on study of 3.5 months and reasons for discontinuation included primary refractory disease, relapse after initial response, proceeding to SCT, patient preference, and death.
The most common treatment-related, nonhematologic AEs were constipation, diarrhea, pneumonitis, nausea, and lung infection. The rate of immune-related AEs was 25% (n = 18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4); 14 responded to steroids and were safely rechallenged with nivolumab, according to the researchers.
Nine patients (13%) discontinued nivolumab (but continued with azacitidine) because of AEs. Two patients died of AEs that were considered possibly related to treatment. One death was caused by progressive pneumonia/pneumonitis, and one was caused by hemophagocytic lymphohistiocytosis.
The overall response rate was 33% (n = 23), with 4 patients achieving a complete response (CR) and 11 achieving a CR with incomplete count recovery (CRi). One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.
The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. Additionally, a higher frequency of pretherapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.
“In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” Dr. Daver said in a statement.
At a median follow-up of 21.4 months, 81% of patients (n = 57) had died; 16 died on study treatment and 41 died after discontinuation. The median OS overall was 6.3 months, and the median event-free survival was 4.5 months.
The median OS was 16.1 months in patients with CR/CRi, partial response, hematologic improvement, or stable disease and 4.1 months in nonresponders (P less than .0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P less than .001).
The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.
Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory AML.
“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Dr. Daver said.
This research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Individual researchers also reported financial relationships with Bristol-Myers Squibb.
SOURCE: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.
FROM CANCER DISCOVERY
Key clinical point:
Major finding: The overall response rate was 33%.
Study details: This phase 2 trial included 70 patients with relapsed/refractory acute myeloid leukemia.
Disclosures: The research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Researchers reported financial relationships with Bristol-Myers Squibb.
Source: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.
P-BCMA-101 gains FDA regenerative medicine designation
(MM), has received the regenerative medicine advanced therapy (RMAT) designation from the Food and Drug Administration.
P-BCMA-101 modifies patients’ T cells using a nonviral DNA modification system known as piggyBac. The modified T cells target cells expressing B-cell maturation antigen (BCMA), which is expressed on essentially all MM cells.
Early results from the phase 1 clinical trial of P-BCMA-101 were recently reported at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, the company developing P-BCMA-101.
Initial results of the trial (NCT03288493) included data on 11 patients with heavily pretreated MM. Patients were a median age of 60, and 73% were high risk. They had a median of six prior therapies.
Patients received conditioning treatment with fludarabine and cyclophosphamide for 3 days prior to receiving P-BCMA-101. They then received one of three doses of CAR T cells – 51×106 (n=3), 152×106 (n=7), or 430×106 (n=1).
The investigators observed no dose-limiting toxicities. Adverse events included neutropenia in eight patients and thrombocytopenia in five.
One patient may have had cytokine release syndrome, but the condition resolved without drug intervention. And investigators observed no neurotoxicity.
Seven of ten patients evaluable for response by International Myeloma Working Group criteria achieved at least a partial response, including very good partial responses and stringent complete response.
The eleventh patient has oligosecretory disease and was only evaluable by PET, which indicated a near-complete response.
Poseida expects to have additional data to report by the end of the year, according to Dr. Ostertag. The study is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.RMAT designation is intended to expedite development and review of regenerative medicines that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
Preliminary evidence must indicate that the therapy has the potential to address unmet medical needs for the disease or condition. RMAT designation includes all the benefits of fast track and breakthrough therapy designations, including early interactions with the FDA.
(MM), has received the regenerative medicine advanced therapy (RMAT) designation from the Food and Drug Administration.
P-BCMA-101 modifies patients’ T cells using a nonviral DNA modification system known as piggyBac. The modified T cells target cells expressing B-cell maturation antigen (BCMA), which is expressed on essentially all MM cells.
Early results from the phase 1 clinical trial of P-BCMA-101 were recently reported at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, the company developing P-BCMA-101.
Initial results of the trial (NCT03288493) included data on 11 patients with heavily pretreated MM. Patients were a median age of 60, and 73% were high risk. They had a median of six prior therapies.
Patients received conditioning treatment with fludarabine and cyclophosphamide for 3 days prior to receiving P-BCMA-101. They then received one of three doses of CAR T cells – 51×106 (n=3), 152×106 (n=7), or 430×106 (n=1).
The investigators observed no dose-limiting toxicities. Adverse events included neutropenia in eight patients and thrombocytopenia in five.
One patient may have had cytokine release syndrome, but the condition resolved without drug intervention. And investigators observed no neurotoxicity.
Seven of ten patients evaluable for response by International Myeloma Working Group criteria achieved at least a partial response, including very good partial responses and stringent complete response.
The eleventh patient has oligosecretory disease and was only evaluable by PET, which indicated a near-complete response.
Poseida expects to have additional data to report by the end of the year, according to Dr. Ostertag. The study is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.RMAT designation is intended to expedite development and review of regenerative medicines that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
Preliminary evidence must indicate that the therapy has the potential to address unmet medical needs for the disease or condition. RMAT designation includes all the benefits of fast track and breakthrough therapy designations, including early interactions with the FDA.
(MM), has received the regenerative medicine advanced therapy (RMAT) designation from the Food and Drug Administration.
P-BCMA-101 modifies patients’ T cells using a nonviral DNA modification system known as piggyBac. The modified T cells target cells expressing B-cell maturation antigen (BCMA), which is expressed on essentially all MM cells.
Early results from the phase 1 clinical trial of P-BCMA-101 were recently reported at the 2018 CAR-TCR Summit by Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, the company developing P-BCMA-101.
Initial results of the trial (NCT03288493) included data on 11 patients with heavily pretreated MM. Patients were a median age of 60, and 73% were high risk. They had a median of six prior therapies.
Patients received conditioning treatment with fludarabine and cyclophosphamide for 3 days prior to receiving P-BCMA-101. They then received one of three doses of CAR T cells – 51×106 (n=3), 152×106 (n=7), or 430×106 (n=1).
The investigators observed no dose-limiting toxicities. Adverse events included neutropenia in eight patients and thrombocytopenia in five.
One patient may have had cytokine release syndrome, but the condition resolved without drug intervention. And investigators observed no neurotoxicity.
Seven of ten patients evaluable for response by International Myeloma Working Group criteria achieved at least a partial response, including very good partial responses and stringent complete response.
The eleventh patient has oligosecretory disease and was only evaluable by PET, which indicated a near-complete response.
Poseida expects to have additional data to report by the end of the year, according to Dr. Ostertag. The study is funded by the California Institute for Regenerative Medicine and Poseida Therapeutics.RMAT designation is intended to expedite development and review of regenerative medicines that are intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition.
Preliminary evidence must indicate that the therapy has the potential to address unmet medical needs for the disease or condition. RMAT designation includes all the benefits of fast track and breakthrough therapy designations, including early interactions with the FDA.
What’s the Impact of Osteoporosis in Multiple Myeloma?
Osteoporosis is common among patients with multiple myeloma (MM), in part because both largely affect older adults. And more than half of MM patients will have MM skeletal-related events, which are painful, and can lead to complications (such as spinal cord compression) and death.
But how does pre-existing bone disease contribute to clinical outcomes in MM? Osteoporosis is a “silent condition” and very little is known about its role in MM, say researchers from The Ohio State University in Columbus and University of Massachusetts in Worcester. The standard diagnostic evaluation for MM does not include dual-energy x-ray absorptiometry, therefore assessments of underlying osteoporosis are not routine. Moreover, it is a challenge to distinguish osteoporotic fragility fractures from pathologic MM-induced fractures. Skeletal surveys underestimate bone involvement by about 40%, the researchers note, and are even less specific for distinguishing myeloma-related secondary osteoporosis from primary osteoporosis.
The researchers examined the relationship between the Fracture Risk Assessment Tool (FRAX) and the risk of death in women who developed MM. They analyzed data from 161,808 women in the Women’s Health Initiative (WHI). Of those, 409 developed MM; 362 had no history of cancer.
At baseline, 98 (27%) women had high FRAX scores, and 264 (73%) had low scores. The median follow-up period was 10.5 years from enrollment and 7.2 years from the time of MM diagnosis. Of the patients with MM, 226 died during the follow-up period, including 71 with high FRAX scores and 155 with low scores. MM mortality was higher among women with high FRAX scores: 72%, vs 59% of those with low scores. Poor bone health was associated with greater MM mortality but was not related to delay in time to diagnosis.
During the evaluation, 57 fractures were reported, 65% before MM diagnosis. Fewer than half of the women had a first fracture after diagnosis. The probability of fracture was similar among the women, regardless of FRAX score. Not surprisingly, older women with lower BMI were most at risk.
The WHI does not include information on staging, chemotherapy, or use of bisphosphonates. Therefore, the impact of bisphosphonates could not be determined in this study. The researchers also did not know how many patients might have had pre-existing monoclonal gammopathy of undetermined significance, a disorder in about 3% of the aging population that progresses to MM in 1% per year.
Source:
Rosko AE, Hade EM, Li W, et al. Clin Lymphoma Myeloma Leuk. 2018;18(9):597-602.
Osteoporosis is common among patients with multiple myeloma (MM), in part because both largely affect older adults. And more than half of MM patients will have MM skeletal-related events, which are painful, and can lead to complications (such as spinal cord compression) and death.
But how does pre-existing bone disease contribute to clinical outcomes in MM? Osteoporosis is a “silent condition” and very little is known about its role in MM, say researchers from The Ohio State University in Columbus and University of Massachusetts in Worcester. The standard diagnostic evaluation for MM does not include dual-energy x-ray absorptiometry, therefore assessments of underlying osteoporosis are not routine. Moreover, it is a challenge to distinguish osteoporotic fragility fractures from pathologic MM-induced fractures. Skeletal surveys underestimate bone involvement by about 40%, the researchers note, and are even less specific for distinguishing myeloma-related secondary osteoporosis from primary osteoporosis.
The researchers examined the relationship between the Fracture Risk Assessment Tool (FRAX) and the risk of death in women who developed MM. They analyzed data from 161,808 women in the Women’s Health Initiative (WHI). Of those, 409 developed MM; 362 had no history of cancer.
At baseline, 98 (27%) women had high FRAX scores, and 264 (73%) had low scores. The median follow-up period was 10.5 years from enrollment and 7.2 years from the time of MM diagnosis. Of the patients with MM, 226 died during the follow-up period, including 71 with high FRAX scores and 155 with low scores. MM mortality was higher among women with high FRAX scores: 72%, vs 59% of those with low scores. Poor bone health was associated with greater MM mortality but was not related to delay in time to diagnosis.
During the evaluation, 57 fractures were reported, 65% before MM diagnosis. Fewer than half of the women had a first fracture after diagnosis. The probability of fracture was similar among the women, regardless of FRAX score. Not surprisingly, older women with lower BMI were most at risk.
The WHI does not include information on staging, chemotherapy, or use of bisphosphonates. Therefore, the impact of bisphosphonates could not be determined in this study. The researchers also did not know how many patients might have had pre-existing monoclonal gammopathy of undetermined significance, a disorder in about 3% of the aging population that progresses to MM in 1% per year.
Source:
Rosko AE, Hade EM, Li W, et al. Clin Lymphoma Myeloma Leuk. 2018;18(9):597-602.
Osteoporosis is common among patients with multiple myeloma (MM), in part because both largely affect older adults. And more than half of MM patients will have MM skeletal-related events, which are painful, and can lead to complications (such as spinal cord compression) and death.
But how does pre-existing bone disease contribute to clinical outcomes in MM? Osteoporosis is a “silent condition” and very little is known about its role in MM, say researchers from The Ohio State University in Columbus and University of Massachusetts in Worcester. The standard diagnostic evaluation for MM does not include dual-energy x-ray absorptiometry, therefore assessments of underlying osteoporosis are not routine. Moreover, it is a challenge to distinguish osteoporotic fragility fractures from pathologic MM-induced fractures. Skeletal surveys underestimate bone involvement by about 40%, the researchers note, and are even less specific for distinguishing myeloma-related secondary osteoporosis from primary osteoporosis.
The researchers examined the relationship between the Fracture Risk Assessment Tool (FRAX) and the risk of death in women who developed MM. They analyzed data from 161,808 women in the Women’s Health Initiative (WHI). Of those, 409 developed MM; 362 had no history of cancer.
At baseline, 98 (27%) women had high FRAX scores, and 264 (73%) had low scores. The median follow-up period was 10.5 years from enrollment and 7.2 years from the time of MM diagnosis. Of the patients with MM, 226 died during the follow-up period, including 71 with high FRAX scores and 155 with low scores. MM mortality was higher among women with high FRAX scores: 72%, vs 59% of those with low scores. Poor bone health was associated with greater MM mortality but was not related to delay in time to diagnosis.
During the evaluation, 57 fractures were reported, 65% before MM diagnosis. Fewer than half of the women had a first fracture after diagnosis. The probability of fracture was similar among the women, regardless of FRAX score. Not surprisingly, older women with lower BMI were most at risk.
The WHI does not include information on staging, chemotherapy, or use of bisphosphonates. Therefore, the impact of bisphosphonates could not be determined in this study. The researchers also did not know how many patients might have had pre-existing monoclonal gammopathy of undetermined significance, a disorder in about 3% of the aging population that progresses to MM in 1% per year.
Source:
Rosko AE, Hade EM, Li W, et al. Clin Lymphoma Myeloma Leuk. 2018;18(9):597-602.
Variant not linked to CLL in Southeast Europe
DUBROVNIK, CROATIA – New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.
Past studies have shown an association between the PTPN22 R620W variant and both CLL and autoimmune diseases in patients from Northwest Europe. However, a new study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.
Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.
“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.
She and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.
The researchers evaluated 320 patients – 168 with CLL, 66 with AIHA, and 86 with ITP – and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.
The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients. For example, minor T allele was 0.107 in CLL, 0.067 in AIHA, 0.036 in ITP, and 0.05 in controls. Similarly, the frequency of the CC genotype was 0.809 in CLL, 0.166 in AIHA, 0.023 in ITP, and 0.901 in controls.
Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.
She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.
Dr. Panovska-Stavridis did not declare any conflicts of interest.
The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Associates, which is owned by the parent company of this news organization.
DUBROVNIK, CROATIA – New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.
Past studies have shown an association between the PTPN22 R620W variant and both CLL and autoimmune diseases in patients from Northwest Europe. However, a new study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.
Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.
“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.
She and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.
The researchers evaluated 320 patients – 168 with CLL, 66 with AIHA, and 86 with ITP – and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.
The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients. For example, minor T allele was 0.107 in CLL, 0.067 in AIHA, 0.036 in ITP, and 0.05 in controls. Similarly, the frequency of the CC genotype was 0.809 in CLL, 0.166 in AIHA, 0.023 in ITP, and 0.901 in controls.
Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.
She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.
Dr. Panovska-Stavridis did not declare any conflicts of interest.
The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Associates, which is owned by the parent company of this news organization.
DUBROVNIK, CROATIA – New research suggests there is no association between the PTPN22 R620W polymorphism and chronic lymphocytic leukemia (CLL) or autoimmune hematologic disorders in patients from the Republic of Macedonia.
Past studies have shown an association between the PTPN22 R620W variant and both CLL and autoimmune diseases in patients from Northwest Europe. However, a new study of Macedonian patients suggests there is no association between the variant and CLL, autoimmune hemolytic anemia (AIHA), or idiopathic thrombocytopenic purpura (ITP) for patients from Southeast Europe.
Irina Panovska-Stavridis, PhD, of Ss. Cyril and Methodius University in Skopje, Republic of Macedonia, and her colleagues presented this finding at Leukemia and Lymphoma, a meeting jointly sponsored by the University of Texas MD Anderson Cancer Center and the School of Medicine at the University of Zagreb, Croatia.
“A lot of data from the literature suggests [the PTPN22 R620W variant ] has a role in developing multiple immune diseases, but it is validated just in patients from Northwest Europe,” Dr. Panovska-Stavridis noted.
She and her colleagues decided to assess the frequency of the PTPN22 R620W variant (C1858T, rs2476601) in individuals from Southeast Europe, particularly the Republic of Macedonia.
The researchers evaluated 320 patients – 168 with CLL, 66 with AIHA, and 86 with ITP – and 182 age- and sex-matched control subjects with no history of malignant or autoimmune disease.
The team found a similar frequency of the minor T allele and genotype distribution in control subjects and patients. For example, minor T allele was 0.107 in CLL, 0.067 in AIHA, 0.036 in ITP, and 0.05 in controls. Similarly, the frequency of the CC genotype was 0.809 in CLL, 0.166 in AIHA, 0.023 in ITP, and 0.901 in controls.
Dr. Panovska-Stavridis said these results suggest the PTPN22 R620W variant is not a risk factor for the development of CLL, AIHA, or ITP in patients from Southeast Europe.
She also said the results suggest the influence of the variant on lymphocytic homeostasis is affected by certain genetic and environmental factors, and the development of CLL and autoimmune diseases is influenced by race/ethnicity-based variations in the germline composition of the IGHV locus in correlation with environmental factors.
Dr. Panovska-Stavridis did not declare any conflicts of interest.
The Leukemia and Lymphoma meeting is organized by Jonathan Wood & Associates, which is owned by the parent company of this news organization.
REPORTING FROM LEUKEMIA AND LYMPHOMA 2018
Key clinical point:
Major finding: The frequency of minor T allele was 0.107 in patients with CLL, 0.067 in patients with autoimmune hemolytic anemia, 0.036 in patients with idiopathic thrombocytopenic purpura, and 0.05 in controls.
Study details: An analysis of the frequency of the PTPN22 R620W variant in 320 individuals from the Republic of Macedonia.
Disclosures: Dr. Panovska-Stavridis did not declare any conflicts of interest.
Researchers consider R/R ALL drugs in the first-line setting
CHICAGO – Novel antibodies are improving outcomes in relapsed and refractory acute lymphoblastic leukemia (ALL), and the hope is that they will also show benefit in the up-front treatment setting and thereby improve overall outcomes, according to Anjali Advani, MD.
“It has been a really exciting time in ALL because several drugs have now been FDA approved: blinatumomab, inotuzumab, and now – for patients who are less than 26 years of age – we actually have CAR [chimeric antigen receptor] T cells that have been approved,” Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic said at the American Society of Hematology Meeting on Hematologic Malignancies.
At the time of relapse, however, the only known cure is allogeneic bone marrow transplant. That may change as more data regarding CAR T cells become available, but the typical goal at this time is to get patients into remission and then to transplant, she said.
Blinatumomab
“Blinatumomab is a very interesting antibody,” Dr. Advani said, explaining that it is a bispecific, T cell–engaging antibody with an anti-CD3 arm that engages the T cell and an anti-CD19 antibody that engages the B lymphoblast.
“Basically this drug then acts as a bridge between the lymphoblast and the T cell to lead to proliferation of the cytotoxic T cell and apoptosis of the lymphoblast,” she said. “It’s interesting because it’s an antibody but it actually works through the immune system through the T cells.”
The largest study to date of blinatumomab in the relapsed/refractory ALL setting showed a 43% complete remission (CR) or CR with partial hematological recovery of peripheral blood counts (CRi) in 189 treated patients with Philadelphia chromosome–negative ALL. It also demonstrated and a 39% rate of salvage status 2 or higher, she said, noting that the response was impressive given that about 30% of participants had a prior transplant (Lancet. 2015 Jan 1;16[1]:57-66).
Of the responders, 40% went on to allogeneic transplant. This was a “fairly impressive” rate given the 30% prior-transplant rate, Dr. Advani said.
“There also was a high minimal residual disease response in those patients achieving CR,” she said, adding that the only significant predictor of response was bone marrow blast count; patients with 50% or more blasts in the bone marrow had a reduced likelihood of responding to blinatumomab.
The agent was approved by the Food and Drug Administration in December 2014 based on these phase 2 findings.
Adverse events mainly included toxicities that are expected in leukemia patients; the most frequent were febrile neutropenia, neutropenia, and anemia. Two patients developed cytokine release syndrome, and about half of the blinatumomab-treated patients experienced neurological events, although the majority of those were grade 1 or 2 and were easily manageable, she noted.
Blinatumomab was further evaluated in the phase 3 TOWER study (NCT02013167), which compared it with standard-of-care chemotherapy regimens. This study showed much higher response rates with blinatumomab than with the chemotherapy regimens (CR with full, partial, or incomplete hematologic recovery, 44% vs. 25%, respectively), Dr. Advani said (N Engl J Med. 2017 Mar 2;376[9]:836-47).
“The main things to remember [are that blinatumomab is] generally very well tolerated and it has been shown to be superior over standard chemotherapy,” she said. “I think it’s a very good drug to use as a bridge to transplant.”
One setting where blinatumomab perhaps should not be used is in patients with central nervous system disease, she noted.
“There is some concern, at least theoretically, that if you have to use concurrent intrathecal chemo along with blinatumomab, there could be some neurotoxicity,” Dr. Advani said, adding that there are no clear data in that setting because patients with CNS disease were not included in the trials.
Patients with high tumor burden may also be poor candidates for blinatumomab because they tend to have lower response rates.
“That doesn’t mean you can’t use it, but you have to kind of think about what the best option would be,” she said.
Additionally, patients treated with CAR T-cell therapy may develop CD19 loss or CD19-negative disease, and blinatumomab should be avoided in these patients.
“The nice thing ... is you don’t have to worry about veno-occlusive disease [VOD] in patients who are proceeding to transplant,” she said, explaining that no increased risk of VOD was seen in these trials.
Inotuzumab
Inotuzumab, which was approved in 2017, differs from blinatumomab in that it is an anti-CD22-calicheamicin conjugate; however, it also showed high response rates in the initial phase 2 trial in relapsed/refractory ALL. The overall response rate was 57%, with 18% achieving a complete response and 63% achieving complete molecular remission.
Of 49 treated patients, 22 patients proceeded to allogeneic transplant, and 5 of those developed VOD.
“Interestingly, four out of five of these patients had received a clofarabine-based preparative regimen, and this likely explains why there was a higher risk of VOD in this study,” she said, noting that the VOD risk has been lower in subsequent studies of inotuzumab.
The international INO-VATE ALL study (NCT01564784) that led to FDA approval was similar in design to the TOWER study in that it compared inotuzumab with standard chemotherapy regimens, and response rates were clearly higher (81% vs. 33%) with inotuzumab (N Engl J Med. 2016 Aug 25;375[8]:740-53).
The VOD risk in the INO-VATE trial was 11%, and it seemed to be higher in those who received dual alkylator–conditioning regimens, which are commonly used in Europe.
Longer-term outcomes after transplant in INO-VATE participants show that median survival has not been reached.
“It’s encouraging that with longer follow-up these patients actually look like they’re doing well,” Dr. Advani said, adding that inotuzumab is a good treatment option for relapsed patients with high disease burden or with CNS disease.
The continuous hookup required for this treatment may be problematic for some younger and older patients, but it is generally not an issue, she noted.
It is important, though, to give as few cycles prior to transplant as possible and to “really think about the preparative regimen to decrease the risk of VOD.”
CAR T-cell therapy
As for CAR T-cell therapy in the relapsed/refractory ALL setting, tisagenlecleucel was approved in 2017 for those up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse.
Approval was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had prior transplant. The confirmed overall remission rate was 82%, with a 63% CR rate and 19% CRi rate.
“This is a very exciting area,” Dr. Advani said. “There are multiple trials being done in adults with ALL to really look at the older subgroup of patients.”
Overall outcomes
“These treatments we have now really seem to be effective in the relapse setting, but the problem is that once patients relapse and then go to transplant, their overall survival is still poor,” Dr. Advani said. “So the question is how can we improve the up-front treatment of patients so that hopefully they don’t relapse, and hopefully we also can send a smaller number of patients to transplant.”
Two trials seek to address this, she said.
The A041501 study (NCT03150693) is comparing C10403 chemotherapy with C10403 induction followed by two cycles of inotuzumab before continuing with chemotherapy in adults under age 40 years with previously untreated B ALL.
The primary objective is improved 3-year event-free survival, she said, adding that minimal residual disease (MRD) testing will be used and that CD20-positive patients will receive rituximab, as is now standard.
The phase 3 E1910 study (NCT02003222) is evaluating up-front blinatumomab in patients aged 30-70 years with newly diagnosed BCR-ABL–negative B-lineage ALL. This trial was complicated by the recent approval of blinatumomab for MRD-positive disease, which rendered randomization of MRD-positive patients unethical. MRD-negative patients will be randomized, however.
“The hope is that, by incorporating blinatumomab up front, this will again improve outcomes for patients,” she said.
Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.
CHICAGO – Novel antibodies are improving outcomes in relapsed and refractory acute lymphoblastic leukemia (ALL), and the hope is that they will also show benefit in the up-front treatment setting and thereby improve overall outcomes, according to Anjali Advani, MD.
“It has been a really exciting time in ALL because several drugs have now been FDA approved: blinatumomab, inotuzumab, and now – for patients who are less than 26 years of age – we actually have CAR [chimeric antigen receptor] T cells that have been approved,” Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic said at the American Society of Hematology Meeting on Hematologic Malignancies.
At the time of relapse, however, the only known cure is allogeneic bone marrow transplant. That may change as more data regarding CAR T cells become available, but the typical goal at this time is to get patients into remission and then to transplant, she said.
Blinatumomab
“Blinatumomab is a very interesting antibody,” Dr. Advani said, explaining that it is a bispecific, T cell–engaging antibody with an anti-CD3 arm that engages the T cell and an anti-CD19 antibody that engages the B lymphoblast.
“Basically this drug then acts as a bridge between the lymphoblast and the T cell to lead to proliferation of the cytotoxic T cell and apoptosis of the lymphoblast,” she said. “It’s interesting because it’s an antibody but it actually works through the immune system through the T cells.”
The largest study to date of blinatumomab in the relapsed/refractory ALL setting showed a 43% complete remission (CR) or CR with partial hematological recovery of peripheral blood counts (CRi) in 189 treated patients with Philadelphia chromosome–negative ALL. It also demonstrated and a 39% rate of salvage status 2 or higher, she said, noting that the response was impressive given that about 30% of participants had a prior transplant (Lancet. 2015 Jan 1;16[1]:57-66).
Of the responders, 40% went on to allogeneic transplant. This was a “fairly impressive” rate given the 30% prior-transplant rate, Dr. Advani said.
“There also was a high minimal residual disease response in those patients achieving CR,” she said, adding that the only significant predictor of response was bone marrow blast count; patients with 50% or more blasts in the bone marrow had a reduced likelihood of responding to blinatumomab.
The agent was approved by the Food and Drug Administration in December 2014 based on these phase 2 findings.
Adverse events mainly included toxicities that are expected in leukemia patients; the most frequent were febrile neutropenia, neutropenia, and anemia. Two patients developed cytokine release syndrome, and about half of the blinatumomab-treated patients experienced neurological events, although the majority of those were grade 1 or 2 and were easily manageable, she noted.
Blinatumomab was further evaluated in the phase 3 TOWER study (NCT02013167), which compared it with standard-of-care chemotherapy regimens. This study showed much higher response rates with blinatumomab than with the chemotherapy regimens (CR with full, partial, or incomplete hematologic recovery, 44% vs. 25%, respectively), Dr. Advani said (N Engl J Med. 2017 Mar 2;376[9]:836-47).
“The main things to remember [are that blinatumomab is] generally very well tolerated and it has been shown to be superior over standard chemotherapy,” she said. “I think it’s a very good drug to use as a bridge to transplant.”
One setting where blinatumomab perhaps should not be used is in patients with central nervous system disease, she noted.
“There is some concern, at least theoretically, that if you have to use concurrent intrathecal chemo along with blinatumomab, there could be some neurotoxicity,” Dr. Advani said, adding that there are no clear data in that setting because patients with CNS disease were not included in the trials.
Patients with high tumor burden may also be poor candidates for blinatumomab because they tend to have lower response rates.
“That doesn’t mean you can’t use it, but you have to kind of think about what the best option would be,” she said.
Additionally, patients treated with CAR T-cell therapy may develop CD19 loss or CD19-negative disease, and blinatumomab should be avoided in these patients.
“The nice thing ... is you don’t have to worry about veno-occlusive disease [VOD] in patients who are proceeding to transplant,” she said, explaining that no increased risk of VOD was seen in these trials.
Inotuzumab
Inotuzumab, which was approved in 2017, differs from blinatumomab in that it is an anti-CD22-calicheamicin conjugate; however, it also showed high response rates in the initial phase 2 trial in relapsed/refractory ALL. The overall response rate was 57%, with 18% achieving a complete response and 63% achieving complete molecular remission.
Of 49 treated patients, 22 patients proceeded to allogeneic transplant, and 5 of those developed VOD.
“Interestingly, four out of five of these patients had received a clofarabine-based preparative regimen, and this likely explains why there was a higher risk of VOD in this study,” she said, noting that the VOD risk has been lower in subsequent studies of inotuzumab.
The international INO-VATE ALL study (NCT01564784) that led to FDA approval was similar in design to the TOWER study in that it compared inotuzumab with standard chemotherapy regimens, and response rates were clearly higher (81% vs. 33%) with inotuzumab (N Engl J Med. 2016 Aug 25;375[8]:740-53).
The VOD risk in the INO-VATE trial was 11%, and it seemed to be higher in those who received dual alkylator–conditioning regimens, which are commonly used in Europe.
Longer-term outcomes after transplant in INO-VATE participants show that median survival has not been reached.
“It’s encouraging that with longer follow-up these patients actually look like they’re doing well,” Dr. Advani said, adding that inotuzumab is a good treatment option for relapsed patients with high disease burden or with CNS disease.
The continuous hookup required for this treatment may be problematic for some younger and older patients, but it is generally not an issue, she noted.
It is important, though, to give as few cycles prior to transplant as possible and to “really think about the preparative regimen to decrease the risk of VOD.”
CAR T-cell therapy
As for CAR T-cell therapy in the relapsed/refractory ALL setting, tisagenlecleucel was approved in 2017 for those up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse.
Approval was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had prior transplant. The confirmed overall remission rate was 82%, with a 63% CR rate and 19% CRi rate.
“This is a very exciting area,” Dr. Advani said. “There are multiple trials being done in adults with ALL to really look at the older subgroup of patients.”
Overall outcomes
“These treatments we have now really seem to be effective in the relapse setting, but the problem is that once patients relapse and then go to transplant, their overall survival is still poor,” Dr. Advani said. “So the question is how can we improve the up-front treatment of patients so that hopefully they don’t relapse, and hopefully we also can send a smaller number of patients to transplant.”
Two trials seek to address this, she said.
The A041501 study (NCT03150693) is comparing C10403 chemotherapy with C10403 induction followed by two cycles of inotuzumab before continuing with chemotherapy in adults under age 40 years with previously untreated B ALL.
The primary objective is improved 3-year event-free survival, she said, adding that minimal residual disease (MRD) testing will be used and that CD20-positive patients will receive rituximab, as is now standard.
The phase 3 E1910 study (NCT02003222) is evaluating up-front blinatumomab in patients aged 30-70 years with newly diagnosed BCR-ABL–negative B-lineage ALL. This trial was complicated by the recent approval of blinatumomab for MRD-positive disease, which rendered randomization of MRD-positive patients unethical. MRD-negative patients will be randomized, however.
“The hope is that, by incorporating blinatumomab up front, this will again improve outcomes for patients,” she said.
Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.
CHICAGO – Novel antibodies are improving outcomes in relapsed and refractory acute lymphoblastic leukemia (ALL), and the hope is that they will also show benefit in the up-front treatment setting and thereby improve overall outcomes, according to Anjali Advani, MD.
“It has been a really exciting time in ALL because several drugs have now been FDA approved: blinatumomab, inotuzumab, and now – for patients who are less than 26 years of age – we actually have CAR [chimeric antigen receptor] T cells that have been approved,” Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic said at the American Society of Hematology Meeting on Hematologic Malignancies.
At the time of relapse, however, the only known cure is allogeneic bone marrow transplant. That may change as more data regarding CAR T cells become available, but the typical goal at this time is to get patients into remission and then to transplant, she said.
Blinatumomab
“Blinatumomab is a very interesting antibody,” Dr. Advani said, explaining that it is a bispecific, T cell–engaging antibody with an anti-CD3 arm that engages the T cell and an anti-CD19 antibody that engages the B lymphoblast.
“Basically this drug then acts as a bridge between the lymphoblast and the T cell to lead to proliferation of the cytotoxic T cell and apoptosis of the lymphoblast,” she said. “It’s interesting because it’s an antibody but it actually works through the immune system through the T cells.”
The largest study to date of blinatumomab in the relapsed/refractory ALL setting showed a 43% complete remission (CR) or CR with partial hematological recovery of peripheral blood counts (CRi) in 189 treated patients with Philadelphia chromosome–negative ALL. It also demonstrated and a 39% rate of salvage status 2 or higher, she said, noting that the response was impressive given that about 30% of participants had a prior transplant (Lancet. 2015 Jan 1;16[1]:57-66).
Of the responders, 40% went on to allogeneic transplant. This was a “fairly impressive” rate given the 30% prior-transplant rate, Dr. Advani said.
“There also was a high minimal residual disease response in those patients achieving CR,” she said, adding that the only significant predictor of response was bone marrow blast count; patients with 50% or more blasts in the bone marrow had a reduced likelihood of responding to blinatumomab.
The agent was approved by the Food and Drug Administration in December 2014 based on these phase 2 findings.
Adverse events mainly included toxicities that are expected in leukemia patients; the most frequent were febrile neutropenia, neutropenia, and anemia. Two patients developed cytokine release syndrome, and about half of the blinatumomab-treated patients experienced neurological events, although the majority of those were grade 1 or 2 and were easily manageable, she noted.
Blinatumomab was further evaluated in the phase 3 TOWER study (NCT02013167), which compared it with standard-of-care chemotherapy regimens. This study showed much higher response rates with blinatumomab than with the chemotherapy regimens (CR with full, partial, or incomplete hematologic recovery, 44% vs. 25%, respectively), Dr. Advani said (N Engl J Med. 2017 Mar 2;376[9]:836-47).
“The main things to remember [are that blinatumomab is] generally very well tolerated and it has been shown to be superior over standard chemotherapy,” she said. “I think it’s a very good drug to use as a bridge to transplant.”
One setting where blinatumomab perhaps should not be used is in patients with central nervous system disease, she noted.
“There is some concern, at least theoretically, that if you have to use concurrent intrathecal chemo along with blinatumomab, there could be some neurotoxicity,” Dr. Advani said, adding that there are no clear data in that setting because patients with CNS disease were not included in the trials.
Patients with high tumor burden may also be poor candidates for blinatumomab because they tend to have lower response rates.
“That doesn’t mean you can’t use it, but you have to kind of think about what the best option would be,” she said.
Additionally, patients treated with CAR T-cell therapy may develop CD19 loss or CD19-negative disease, and blinatumomab should be avoided in these patients.
“The nice thing ... is you don’t have to worry about veno-occlusive disease [VOD] in patients who are proceeding to transplant,” she said, explaining that no increased risk of VOD was seen in these trials.
Inotuzumab
Inotuzumab, which was approved in 2017, differs from blinatumomab in that it is an anti-CD22-calicheamicin conjugate; however, it also showed high response rates in the initial phase 2 trial in relapsed/refractory ALL. The overall response rate was 57%, with 18% achieving a complete response and 63% achieving complete molecular remission.
Of 49 treated patients, 22 patients proceeded to allogeneic transplant, and 5 of those developed VOD.
“Interestingly, four out of five of these patients had received a clofarabine-based preparative regimen, and this likely explains why there was a higher risk of VOD in this study,” she said, noting that the VOD risk has been lower in subsequent studies of inotuzumab.
The international INO-VATE ALL study (NCT01564784) that led to FDA approval was similar in design to the TOWER study in that it compared inotuzumab with standard chemotherapy regimens, and response rates were clearly higher (81% vs. 33%) with inotuzumab (N Engl J Med. 2016 Aug 25;375[8]:740-53).
The VOD risk in the INO-VATE trial was 11%, and it seemed to be higher in those who received dual alkylator–conditioning regimens, which are commonly used in Europe.
Longer-term outcomes after transplant in INO-VATE participants show that median survival has not been reached.
“It’s encouraging that with longer follow-up these patients actually look like they’re doing well,” Dr. Advani said, adding that inotuzumab is a good treatment option for relapsed patients with high disease burden or with CNS disease.
The continuous hookup required for this treatment may be problematic for some younger and older patients, but it is generally not an issue, she noted.
It is important, though, to give as few cycles prior to transplant as possible and to “really think about the preparative regimen to decrease the risk of VOD.”
CAR T-cell therapy
As for CAR T-cell therapy in the relapsed/refractory ALL setting, tisagenlecleucel was approved in 2017 for those up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse.
Approval was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had prior transplant. The confirmed overall remission rate was 82%, with a 63% CR rate and 19% CRi rate.
“This is a very exciting area,” Dr. Advani said. “There are multiple trials being done in adults with ALL to really look at the older subgroup of patients.”
Overall outcomes
“These treatments we have now really seem to be effective in the relapse setting, but the problem is that once patients relapse and then go to transplant, their overall survival is still poor,” Dr. Advani said. “So the question is how can we improve the up-front treatment of patients so that hopefully they don’t relapse, and hopefully we also can send a smaller number of patients to transplant.”
Two trials seek to address this, she said.
The A041501 study (NCT03150693) is comparing C10403 chemotherapy with C10403 induction followed by two cycles of inotuzumab before continuing with chemotherapy in adults under age 40 years with previously untreated B ALL.
The primary objective is improved 3-year event-free survival, she said, adding that minimal residual disease (MRD) testing will be used and that CD20-positive patients will receive rituximab, as is now standard.
The phase 3 E1910 study (NCT02003222) is evaluating up-front blinatumomab in patients aged 30-70 years with newly diagnosed BCR-ABL–negative B-lineage ALL. This trial was complicated by the recent approval of blinatumomab for MRD-positive disease, which rendered randomization of MRD-positive patients unethical. MRD-negative patients will be randomized, however.
“The hope is that, by incorporating blinatumomab up front, this will again improve outcomes for patients,” she said.
Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.
EXPERT ANALYSIS FROM MHM 2018
Will quad therapy become the new standard in myeloma?
NEW YORK – , though data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center, Madison.
“The outlook for myeloma patients is quite good,” Dr. Callander said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
“Triplet therapy is the standard, and quad therapy may be in the future.”
The study that set the standard for triplets in myeloma, according to Dr. Callander, is SWOG 0777, an open-label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.
Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable (Lancet. 2017 Feb 4;389[10068]:519-27).
The median progression-free survival was 43 months for the triplet, versus 30 months for the two-drug regimen (P = .0018); likewise, median overall survival was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P = .025).
“Very convincingly, just receiving that short exposure to bortezomib ended up causing a substantial increase of progression-free and overall survival,” Dr. Callander said.
The efficacy of multiple triplet regimens has been documented, including the combination of carfilzomib, lenalidomide, and dexamethasone (KRd); cyclophosphamide, bortezomib, and dexamethasone (CyBorD); and more recently, ixazomib, lenalidomide, and dexamethasone (IRd). These regimens have “excellent” response rates and survival data, Dr. Callander said.
Data is now emerging on the potential role of four-drug combinations, she added. The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at the 2017 annual meeting of the American Society of Clinical Oncology.
Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data presented at ASCO in 2017, with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.
Even so, “it remains to be seen whether four drugs will be the new standard,” Dr. Callander told the NCCN attendees.
Four- versus three-drug strategies are being evaluated in ongoing randomized clinical trials, including patients with previously untreated myeloma, she said. Those studies include Cassiopeia, which is evaluating bortezomib, thalidomide, and dexamethasone (with or without daratumumab), and GRIFFIN, which is looking at VRd (with or without daratumumab).
Daratumumab recently received an additional indication in the treatment of myeloma, this time as part of a four-drug regimen, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.
The Food and Drug Administration approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.
That approval was based on results of the multicenter phase 3 ALCYONE study, showing an 18-month progression-free survival rate of 71.6% for the four-drug combination versus 50.2% for VMP alone (N Engl J Med. 2018;378:518-28).
Dr. Callander reported having no relevant financial disclosures.
NEW YORK – , though data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center, Madison.
“The outlook for myeloma patients is quite good,” Dr. Callander said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
“Triplet therapy is the standard, and quad therapy may be in the future.”
The study that set the standard for triplets in myeloma, according to Dr. Callander, is SWOG 0777, an open-label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.
Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable (Lancet. 2017 Feb 4;389[10068]:519-27).
The median progression-free survival was 43 months for the triplet, versus 30 months for the two-drug regimen (P = .0018); likewise, median overall survival was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P = .025).
“Very convincingly, just receiving that short exposure to bortezomib ended up causing a substantial increase of progression-free and overall survival,” Dr. Callander said.
The efficacy of multiple triplet regimens has been documented, including the combination of carfilzomib, lenalidomide, and dexamethasone (KRd); cyclophosphamide, bortezomib, and dexamethasone (CyBorD); and more recently, ixazomib, lenalidomide, and dexamethasone (IRd). These regimens have “excellent” response rates and survival data, Dr. Callander said.
Data is now emerging on the potential role of four-drug combinations, she added. The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at the 2017 annual meeting of the American Society of Clinical Oncology.
Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data presented at ASCO in 2017, with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.
Even so, “it remains to be seen whether four drugs will be the new standard,” Dr. Callander told the NCCN attendees.
Four- versus three-drug strategies are being evaluated in ongoing randomized clinical trials, including patients with previously untreated myeloma, she said. Those studies include Cassiopeia, which is evaluating bortezomib, thalidomide, and dexamethasone (with or without daratumumab), and GRIFFIN, which is looking at VRd (with or without daratumumab).
Daratumumab recently received an additional indication in the treatment of myeloma, this time as part of a four-drug regimen, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.
The Food and Drug Administration approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.
That approval was based on results of the multicenter phase 3 ALCYONE study, showing an 18-month progression-free survival rate of 71.6% for the four-drug combination versus 50.2% for VMP alone (N Engl J Med. 2018;378:518-28).
Dr. Callander reported having no relevant financial disclosures.
NEW YORK – , though data from additional randomized trials are needed to define their role in clinical practice, according to Natalie S. Callander, MD, of the University of Wisconsin Carbone Cancer Center, Madison.
“The outlook for myeloma patients is quite good,” Dr. Callander said at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
“Triplet therapy is the standard, and quad therapy may be in the future.”
The study that set the standard for triplets in myeloma, according to Dr. Callander, is SWOG 0777, an open-label, phase 3 trial that compared bortezomib with lenalidomide and dexamethasone (VRd) to lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma.
Adding bortezomib to lenalidomide and dexamethasone significantly improved both progression-free and overall survival in the 525-patient trial, with a risk-benefit profile that was acceptable (Lancet. 2017 Feb 4;389[10068]:519-27).
The median progression-free survival was 43 months for the triplet, versus 30 months for the two-drug regimen (P = .0018); likewise, median overall survival was significantly improved, at 75 months versus 64 months for triplet versus doublet therapy (P = .025).
“Very convincingly, just receiving that short exposure to bortezomib ended up causing a substantial increase of progression-free and overall survival,” Dr. Callander said.
The efficacy of multiple triplet regimens has been documented, including the combination of carfilzomib, lenalidomide, and dexamethasone (KRd); cyclophosphamide, bortezomib, and dexamethasone (CyBorD); and more recently, ixazomib, lenalidomide, and dexamethasone (IRd). These regimens have “excellent” response rates and survival data, Dr. Callander said.
Data is now emerging on the potential role of four-drug combinations, she added. The combination of elotuzumab plus VRd produced high response rates that were even higher after transplant, with reasonable toxicity, Dr. Callander said of phase 2 trial data presented at the 2017 annual meeting of the American Society of Clinical Oncology.
Similarly, the combination of daratumumab plus KRd had a 100% rate of partial response or better in phase 2 data presented at ASCO in 2017, with rates of very good partial response and complete response that improved with successive cycles of therapy, she said.
Even so, “it remains to be seen whether four drugs will be the new standard,” Dr. Callander told the NCCN attendees.
Four- versus three-drug strategies are being evaluated in ongoing randomized clinical trials, including patients with previously untreated myeloma, she said. Those studies include Cassiopeia, which is evaluating bortezomib, thalidomide, and dexamethasone (with or without daratumumab), and GRIFFIN, which is looking at VRd (with or without daratumumab).
Daratumumab recently received an additional indication in the treatment of myeloma, this time as part of a four-drug regimen, Dr. Callander added in a discussion on treatment options for elderly myeloma patients.
The Food and Drug Administration approved the monoclonal antibody in combination with bortezomib, melphalan, and prednisone (VMP) for treatment of newly diagnosed myeloma patients who are transplant ineligible.
That approval was based on results of the multicenter phase 3 ALCYONE study, showing an 18-month progression-free survival rate of 71.6% for the four-drug combination versus 50.2% for VMP alone (N Engl J Med. 2018;378:518-28).
Dr. Callander reported having no relevant financial disclosures.
EXPERT ANALYSIS FROM NCCN HEMATOLOGIC MALIGNANCIES
Real-world clues for optimal sequencing of CLL novel agents
NEW YORK – Although optimal sequencing strategies in chronic lymphocytic leukemia are still unclear, real-world data suggest an alternate kinase inhibitor or venetoclax is the best approach for a patient who has received ibrutinib or idelalisib, according to John N. Allan, MD, of Cornell University, New York.
“I think for the most part, there’s enough evidence,” Dr. Allan said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.
“If you had one to two lines of therapy, it still favors the novel agents rather than the chemotherapy arms in all these studies,” said Dr. Allan, referring to some of the pivotal trials supporting approval of novel agents in chronic lymphocytic leukemia (CLL). “The earlier we get to these drugs, I believe, the better.”
While venetoclax after ibrutinib is supported by multiple studies, “vice versa is unknown, but there’s seemingly no reason to think it wouldn’t work – different mechanisms of actions, different pathways,” Dr. Allan said.
What is clear, he added, is that retreating those patients with chemoimmunotherapy is not optimal.
In support of that, he cited a multicenter retrospective analysis, which is believed to be the largest real-world experience to date of novel agents in CLL looking at post–kinase inhibitor salvage strategies (Ann Oncol. 2017 May 1;28[5]:1050-6).
Using an alternate kinase inhibitor or venetoclax resulted in superior progression-free survival versus chemoimmunotherapy at the time of initial kinase inhibitor failure in that study, which looked at treatment strategies and outcomes for 683 patients.
Ibrutinib appeared to be superior to idelalisib as a first kinase inhibitor, with significantly better progression-free survival in both frontline and relapsed/refractory settings, and in both complex karyotype and del17p patients, according to the report. Additionally, the response rate to venetoclax seemed superior to that of idelalisib in patients who discontinued ibrutinib because of progression or toxicity.
All of that supports the need for trials to test various sequencing strategies and establish clear treatment algorithms, according to Dr. Allan. “Optimal sequencing is unknown, but real-world data gives us some idea.”
For relapsed/refractory patients, ibrutinib, idelalisib, and venetoclax all have lengthened responses, improved survival, and are approved by the Food and Drug Administration, he added, noting that the toxicity profiles vary and must be understood when dosing and prescribing these agents.
More novel treatments are on the way. On Sept. 24, just days after Dr. Allan’s NCCN presentation, the FDA granted approval to duvelisib for adults with relapsed or refractory CLL or small lymphocytic lymphoma following two or more previous lines of therapy.
Dr. Allan reported financial disclosures related to AbbVie, Acerta Pharma, Genentech, Pharmacyclics, Sunesis Pharmaceuticals, and Verastem Oncology.
NEW YORK – Although optimal sequencing strategies in chronic lymphocytic leukemia are still unclear, real-world data suggest an alternate kinase inhibitor or venetoclax is the best approach for a patient who has received ibrutinib or idelalisib, according to John N. Allan, MD, of Cornell University, New York.
“I think for the most part, there’s enough evidence,” Dr. Allan said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.
“If you had one to two lines of therapy, it still favors the novel agents rather than the chemotherapy arms in all these studies,” said Dr. Allan, referring to some of the pivotal trials supporting approval of novel agents in chronic lymphocytic leukemia (CLL). “The earlier we get to these drugs, I believe, the better.”
While venetoclax after ibrutinib is supported by multiple studies, “vice versa is unknown, but there’s seemingly no reason to think it wouldn’t work – different mechanisms of actions, different pathways,” Dr. Allan said.
What is clear, he added, is that retreating those patients with chemoimmunotherapy is not optimal.
In support of that, he cited a multicenter retrospective analysis, which is believed to be the largest real-world experience to date of novel agents in CLL looking at post–kinase inhibitor salvage strategies (Ann Oncol. 2017 May 1;28[5]:1050-6).
Using an alternate kinase inhibitor or venetoclax resulted in superior progression-free survival versus chemoimmunotherapy at the time of initial kinase inhibitor failure in that study, which looked at treatment strategies and outcomes for 683 patients.
Ibrutinib appeared to be superior to idelalisib as a first kinase inhibitor, with significantly better progression-free survival in both frontline and relapsed/refractory settings, and in both complex karyotype and del17p patients, according to the report. Additionally, the response rate to venetoclax seemed superior to that of idelalisib in patients who discontinued ibrutinib because of progression or toxicity.
All of that supports the need for trials to test various sequencing strategies and establish clear treatment algorithms, according to Dr. Allan. “Optimal sequencing is unknown, but real-world data gives us some idea.”
For relapsed/refractory patients, ibrutinib, idelalisib, and venetoclax all have lengthened responses, improved survival, and are approved by the Food and Drug Administration, he added, noting that the toxicity profiles vary and must be understood when dosing and prescribing these agents.
More novel treatments are on the way. On Sept. 24, just days after Dr. Allan’s NCCN presentation, the FDA granted approval to duvelisib for adults with relapsed or refractory CLL or small lymphocytic lymphoma following two or more previous lines of therapy.
Dr. Allan reported financial disclosures related to AbbVie, Acerta Pharma, Genentech, Pharmacyclics, Sunesis Pharmaceuticals, and Verastem Oncology.
NEW YORK – Although optimal sequencing strategies in chronic lymphocytic leukemia are still unclear, real-world data suggest an alternate kinase inhibitor or venetoclax is the best approach for a patient who has received ibrutinib or idelalisib, according to John N. Allan, MD, of Cornell University, New York.
“I think for the most part, there’s enough evidence,” Dr. Allan said at the annual congress on Hematologic Malignancies held by the National Comprehensive Cancer Network.
“If you had one to two lines of therapy, it still favors the novel agents rather than the chemotherapy arms in all these studies,” said Dr. Allan, referring to some of the pivotal trials supporting approval of novel agents in chronic lymphocytic leukemia (CLL). “The earlier we get to these drugs, I believe, the better.”
While venetoclax after ibrutinib is supported by multiple studies, “vice versa is unknown, but there’s seemingly no reason to think it wouldn’t work – different mechanisms of actions, different pathways,” Dr. Allan said.
What is clear, he added, is that retreating those patients with chemoimmunotherapy is not optimal.
In support of that, he cited a multicenter retrospective analysis, which is believed to be the largest real-world experience to date of novel agents in CLL looking at post–kinase inhibitor salvage strategies (Ann Oncol. 2017 May 1;28[5]:1050-6).
Using an alternate kinase inhibitor or venetoclax resulted in superior progression-free survival versus chemoimmunotherapy at the time of initial kinase inhibitor failure in that study, which looked at treatment strategies and outcomes for 683 patients.
Ibrutinib appeared to be superior to idelalisib as a first kinase inhibitor, with significantly better progression-free survival in both frontline and relapsed/refractory settings, and in both complex karyotype and del17p patients, according to the report. Additionally, the response rate to venetoclax seemed superior to that of idelalisib in patients who discontinued ibrutinib because of progression or toxicity.
All of that supports the need for trials to test various sequencing strategies and establish clear treatment algorithms, according to Dr. Allan. “Optimal sequencing is unknown, but real-world data gives us some idea.”
For relapsed/refractory patients, ibrutinib, idelalisib, and venetoclax all have lengthened responses, improved survival, and are approved by the Food and Drug Administration, he added, noting that the toxicity profiles vary and must be understood when dosing and prescribing these agents.
More novel treatments are on the way. On Sept. 24, just days after Dr. Allan’s NCCN presentation, the FDA granted approval to duvelisib for adults with relapsed or refractory CLL or small lymphocytic lymphoma following two or more previous lines of therapy.
Dr. Allan reported financial disclosures related to AbbVie, Acerta Pharma, Genentech, Pharmacyclics, Sunesis Pharmaceuticals, and Verastem Oncology.
EXPERT ANALYSIS FROM NCCN HEMATOLOGIC MALIGNANCIES CONGRESS