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Company narrows focus of development for tazemetostat
Epizyme, Inc., has announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with diffuse large B-cell lymphoma (DLBCL).
However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.
Tazemetostat is an EZH2 inhibitor being developed to treat multiple hematologic and solid tumor malignancies.
Epizyme has been conducting a phase 1/2 trial of tazemetostat in patients with relapsed and/or refractory DLBCL as well as other B-cell lymphomas and solid tumors (NCT01897571).
The trial includes DLBCL patients with and without EZH2 activating mutations. Some patients were assigned to receive tazemetostat monotherapy, and some were assigned to tazemetostat in combination with prednisolone.
Epizyme has conducted an interim assessment of data from this trial and concluded that the clinical activity observed “is not sufficient to warrant further development of tazemetostat in DLBCL as a monotherapy or in combination with prednisolone.”
Epizyme said it plans to present data from this trial at a medical meeting in the second half of 2018.
The company is still conducting other studies of tazemetostat in patients with DLBCL.
In one study (NCT02889523), Epizyme and the Lymphoma Academic Research Organisation are evaluating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) in patients with newly diagnosed DLBCL.
In another study (NCT03028103), Epizyme is evaluating tazemetostat in combination with fluconazole or omeprazole and repaglinide in patients with relapsed/refractory DLBCL, other B-cell lymphomas, or solid tumor malignancies.
Epizyme, Inc., has announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with diffuse large B-cell lymphoma (DLBCL).
However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.
Tazemetostat is an EZH2 inhibitor being developed to treat multiple hematologic and solid tumor malignancies.
Epizyme has been conducting a phase 1/2 trial of tazemetostat in patients with relapsed and/or refractory DLBCL as well as other B-cell lymphomas and solid tumors (NCT01897571).
The trial includes DLBCL patients with and without EZH2 activating mutations. Some patients were assigned to receive tazemetostat monotherapy, and some were assigned to tazemetostat in combination with prednisolone.
Epizyme has conducted an interim assessment of data from this trial and concluded that the clinical activity observed “is not sufficient to warrant further development of tazemetostat in DLBCL as a monotherapy or in combination with prednisolone.”
Epizyme said it plans to present data from this trial at a medical meeting in the second half of 2018.
The company is still conducting other studies of tazemetostat in patients with DLBCL.
In one study (NCT02889523), Epizyme and the Lymphoma Academic Research Organisation are evaluating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) in patients with newly diagnosed DLBCL.
In another study (NCT03028103), Epizyme is evaluating tazemetostat in combination with fluconazole or omeprazole and repaglinide in patients with relapsed/refractory DLBCL, other B-cell lymphomas, or solid tumor malignancies.
Epizyme, Inc., has announced its decision to stop developing tazemetostat for use as monotherapy or in combination with prednisolone for patients with diffuse large B-cell lymphoma (DLBCL).
However, tazemetostat is still under investigation as a potential treatment for DLBCL as part of other combination regimens.
Tazemetostat is an EZH2 inhibitor being developed to treat multiple hematologic and solid tumor malignancies.
Epizyme has been conducting a phase 1/2 trial of tazemetostat in patients with relapsed and/or refractory DLBCL as well as other B-cell lymphomas and solid tumors (NCT01897571).
The trial includes DLBCL patients with and without EZH2 activating mutations. Some patients were assigned to receive tazemetostat monotherapy, and some were assigned to tazemetostat in combination with prednisolone.
Epizyme has conducted an interim assessment of data from this trial and concluded that the clinical activity observed “is not sufficient to warrant further development of tazemetostat in DLBCL as a monotherapy or in combination with prednisolone.”
Epizyme said it plans to present data from this trial at a medical meeting in the second half of 2018.
The company is still conducting other studies of tazemetostat in patients with DLBCL.
In one study (NCT02889523), Epizyme and the Lymphoma Academic Research Organisation are evaluating tazemetostat in combination with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) in patients with newly diagnosed DLBCL.
In another study (NCT03028103), Epizyme is evaluating tazemetostat in combination with fluconazole or omeprazole and repaglinide in patients with relapsed/refractory DLBCL, other B-cell lymphomas, or solid tumor malignancies.
PET/CT accurately predicts MCL stage
Bone marrow involvement in mantle cell lymphoma could be assessed using just 18fluorodeoxyglucose (FDG)–PET/CT, according to findings from a small, retrospective study published in Clinical Lymphoma, Myeloma & Leukemia.
Rustain Morgan, MD, of the University of Colorado, Aurora, and his colleagues found that, at a certain threshold of bone marrow voxels in standard uptake value (SUV), there was 100% sensitivity and 80% specificity in determining bone marrow involvement in mantle cell lymphoma (MCL).
Currently, National Comprehensive Cancer Network guidelines call for bone marrow biopsy and whole body FDG PET/CT scan to complete an initial diagnosis of MCL.
“One of the most important factors for correct staging is the identification of bone marrow involvement, occurring in approximately 55% of patients with MCL, which classifies patients as advanced stage. However, accurate analysis of bone marrow involvement can be challenging due to sampling error,” the researchers wrote. “While bone marrow biopsy remains the gold standard, it is not a perfect standard given unilateral variability.”
In previous studies, FDG PET/CT was not considered sensitive enough to detect gastrointestinal or bone marrow involvement. However, these earlier studies used SUV maximum or mean or a visual assessment of the bone marrow activity, compared with hepatic uptake. To address this issue, the researchers developed a new method of examining SUV distribution throughout the pelvic bones by analyzing thousands of bone marrow voxels within the bilateral iliacs.
During the developmental phase, an institutional dataset of 11 patients with MCL was used to define the voxel-based analysis. These patients had undergone both unilateral iliac bone marrow biopsy and FDG PET/CT at the initial diagnosis. Then, FDG PET/CT scans from another 12 patients with MCL from a different institution were used to validate the developmental phase findings. Finally, a control group of 5 people with no known malignancy were referred for FDG PET/CT pulmonary nodule evaluation.
“The hypothesis of the study was that, if the bone marrow was involved by lymphoma, then there would be a small increase in the SUV of each voxel, reflecting involvement by the lymphoma. In order to capture such changes, we analyzed the percent of total voxels in SUV ranging from 0.75 to 1.20, in increments of 0.05, as this is where the greatest divergence was visually identified,” the researchers wrote. “The goal was to identify if a percentage of voxels at a set SUV could detect lymphomatous involvement.”
The researchers identified 10 candidate thresholds in the developmental phase; 4 of these performed better than the others in the validation phase. Using those thresholds, 10 of the 12 patients in the validation cohort could be correctly staged using FDG PET/CT.
Further analysis identified a single threshold that performed best: If greater than 38% of the voxels (averaging 1,734 voxels) demonstrated an SUV of less than 0.95, the sensitivity was 100% and the specificity was 80%.
The researchers acknowledged that the findings are limited because of the study’s small sample size and said the results should be validated in a larger trial.
There was no external funding for the study and the researchers reported having no financial disclosures.
SOURCE: Morgan R et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 4. doi: 10.1016/j.clml.2018.06.024.
Bone marrow involvement in mantle cell lymphoma could be assessed using just 18fluorodeoxyglucose (FDG)–PET/CT, according to findings from a small, retrospective study published in Clinical Lymphoma, Myeloma & Leukemia.
Rustain Morgan, MD, of the University of Colorado, Aurora, and his colleagues found that, at a certain threshold of bone marrow voxels in standard uptake value (SUV), there was 100% sensitivity and 80% specificity in determining bone marrow involvement in mantle cell lymphoma (MCL).
Currently, National Comprehensive Cancer Network guidelines call for bone marrow biopsy and whole body FDG PET/CT scan to complete an initial diagnosis of MCL.
“One of the most important factors for correct staging is the identification of bone marrow involvement, occurring in approximately 55% of patients with MCL, which classifies patients as advanced stage. However, accurate analysis of bone marrow involvement can be challenging due to sampling error,” the researchers wrote. “While bone marrow biopsy remains the gold standard, it is not a perfect standard given unilateral variability.”
In previous studies, FDG PET/CT was not considered sensitive enough to detect gastrointestinal or bone marrow involvement. However, these earlier studies used SUV maximum or mean or a visual assessment of the bone marrow activity, compared with hepatic uptake. To address this issue, the researchers developed a new method of examining SUV distribution throughout the pelvic bones by analyzing thousands of bone marrow voxels within the bilateral iliacs.
During the developmental phase, an institutional dataset of 11 patients with MCL was used to define the voxel-based analysis. These patients had undergone both unilateral iliac bone marrow biopsy and FDG PET/CT at the initial diagnosis. Then, FDG PET/CT scans from another 12 patients with MCL from a different institution were used to validate the developmental phase findings. Finally, a control group of 5 people with no known malignancy were referred for FDG PET/CT pulmonary nodule evaluation.
“The hypothesis of the study was that, if the bone marrow was involved by lymphoma, then there would be a small increase in the SUV of each voxel, reflecting involvement by the lymphoma. In order to capture such changes, we analyzed the percent of total voxels in SUV ranging from 0.75 to 1.20, in increments of 0.05, as this is where the greatest divergence was visually identified,” the researchers wrote. “The goal was to identify if a percentage of voxels at a set SUV could detect lymphomatous involvement.”
The researchers identified 10 candidate thresholds in the developmental phase; 4 of these performed better than the others in the validation phase. Using those thresholds, 10 of the 12 patients in the validation cohort could be correctly staged using FDG PET/CT.
Further analysis identified a single threshold that performed best: If greater than 38% of the voxels (averaging 1,734 voxels) demonstrated an SUV of less than 0.95, the sensitivity was 100% and the specificity was 80%.
The researchers acknowledged that the findings are limited because of the study’s small sample size and said the results should be validated in a larger trial.
There was no external funding for the study and the researchers reported having no financial disclosures.
SOURCE: Morgan R et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 4. doi: 10.1016/j.clml.2018.06.024.
Bone marrow involvement in mantle cell lymphoma could be assessed using just 18fluorodeoxyglucose (FDG)–PET/CT, according to findings from a small, retrospective study published in Clinical Lymphoma, Myeloma & Leukemia.
Rustain Morgan, MD, of the University of Colorado, Aurora, and his colleagues found that, at a certain threshold of bone marrow voxels in standard uptake value (SUV), there was 100% sensitivity and 80% specificity in determining bone marrow involvement in mantle cell lymphoma (MCL).
Currently, National Comprehensive Cancer Network guidelines call for bone marrow biopsy and whole body FDG PET/CT scan to complete an initial diagnosis of MCL.
“One of the most important factors for correct staging is the identification of bone marrow involvement, occurring in approximately 55% of patients with MCL, which classifies patients as advanced stage. However, accurate analysis of bone marrow involvement can be challenging due to sampling error,” the researchers wrote. “While bone marrow biopsy remains the gold standard, it is not a perfect standard given unilateral variability.”
In previous studies, FDG PET/CT was not considered sensitive enough to detect gastrointestinal or bone marrow involvement. However, these earlier studies used SUV maximum or mean or a visual assessment of the bone marrow activity, compared with hepatic uptake. To address this issue, the researchers developed a new method of examining SUV distribution throughout the pelvic bones by analyzing thousands of bone marrow voxels within the bilateral iliacs.
During the developmental phase, an institutional dataset of 11 patients with MCL was used to define the voxel-based analysis. These patients had undergone both unilateral iliac bone marrow biopsy and FDG PET/CT at the initial diagnosis. Then, FDG PET/CT scans from another 12 patients with MCL from a different institution were used to validate the developmental phase findings. Finally, a control group of 5 people with no known malignancy were referred for FDG PET/CT pulmonary nodule evaluation.
“The hypothesis of the study was that, if the bone marrow was involved by lymphoma, then there would be a small increase in the SUV of each voxel, reflecting involvement by the lymphoma. In order to capture such changes, we analyzed the percent of total voxels in SUV ranging from 0.75 to 1.20, in increments of 0.05, as this is where the greatest divergence was visually identified,” the researchers wrote. “The goal was to identify if a percentage of voxels at a set SUV could detect lymphomatous involvement.”
The researchers identified 10 candidate thresholds in the developmental phase; 4 of these performed better than the others in the validation phase. Using those thresholds, 10 of the 12 patients in the validation cohort could be correctly staged using FDG PET/CT.
Further analysis identified a single threshold that performed best: If greater than 38% of the voxels (averaging 1,734 voxels) demonstrated an SUV of less than 0.95, the sensitivity was 100% and the specificity was 80%.
The researchers acknowledged that the findings are limited because of the study’s small sample size and said the results should be validated in a larger trial.
There was no external funding for the study and the researchers reported having no financial disclosures.
SOURCE: Morgan R et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 4. doi: 10.1016/j.clml.2018.06.024.
REPORTING FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: If greater than 38% of the voxels demonstrated an standard uptake value of less than 0.95, there was a sensitivity of 100% and a specificity of 80%.
Study details: A retrospective cohort study of 23 patients with mantle cell leukemia and 5 controls.
Disclosures: There was no external funding for the study and the researchers reported having no financial disclosures.
Source: Morgan R et al. Clin Lymphoma Myeloma Leuk. 2018 Jul 4. doi: 10.1016/j.clml.2018.06.024.
Treatment improves PFS in early stage FL
A multidrug regimen can improve upon involved-field radiotherapy (IFRT) in patients with early stage follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.
FL patients who received IFRT plus cyclophosphamide, vincristine, and prednisolone (CVP)—with or without rituximab—had a significant improvement in progression-free survival (PFS) compared to patients who received standard treatment with IFRT alone.
However, there was no significant difference in overall survival (OS) between the treatment arms.
“This is the first successful randomized study ever to be conducted in early stage follicular lymphoma comparing standard therapy to standard therapy plus effective chemotherapy or immunochemotherapy,” said Michael MacManus, MBBCh, of Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
“It shows that the initial treatment received by patients can significantly affect their long-term chance of staying free from disease. Moving forward, we are interested in determining whether there is a benefit in overall long-term survival for patients treated with the combination with further follow-up, and if there is any way to predict if a person will benefit from combined treatment based on analyses of blood or biopsy specimens.”
Dr MacManus and his colleagues studied 150 patients with stage I to II, low-grade FL who were enrolled in this trial between 2000 and 2012.
At randomization, the patients’ median age was 57, 52% were male, 75% had stage I disease, and 48% had PET staging.
Half of patients (n=75) were randomized to receive IFRT (30-36 Gy) alone, and half were randomized to IFRT (30-36 Gy) plus 6 cycles of CVP. From 2006 on, patients in the CVP arm received rituximab (R) as well (n=31).
Baseline characteristics were well-balanced between the treatment arms.
Efficacy
The median follow-up was 9.6 years (range, 3.1 to 15.8 years).
PFS was significantly better among patients randomized to receive CVP±R (hazard ratio [HR]=0.57; P=0.033). The estimated 10-year PFS rate was 41% in the IFRT arm and 59% in the CVP±R arm.
Patients randomized to receive CVP plus R (n=31) had significantly better PFS than patients randomized to receive IFRT alone (n=31) over the same time period (HR=0.26; P=0.045).
There were 10 deaths in the IRFT arm and 5 in the CVP±R arm, but there was no significant difference in OS between the arms (HR=0.62; P=0.40). The 10-year OS rate was 86% in the IFRT arm and 95% in the CVP±R arm.
There was no significant between-arm difference in transformation to aggressive lymphoma (P=0.1). Transformation occurred in 10 patients in the IFRT arm and 4 in the CVP±R arm.
Safety
There were 148 patients from both arms who ultimately received IFRT, and 69 patients who received CVP±R.
Grade 2 toxicities occurring in more than 10% of IFRT recipients included upper gastrointestinal (n=27; 18%), skin (n=21; 14%), and mucous membrane (n=19; 12%) toxicity. One IFRT recipient had grade 3 mucositis, and 1 had grade 4 esophageal/pharyngeal mucosal toxicity.
Grade 3 toxicities occurring in at least 2 patients in the CVP±R arm included neutropenia (n=10; 14%), infection (n=8; 12%), diarrhea (n=3; 4%), elevated gamma-glutamyl transferase (n=3; 4%), fatigue (n=3; 4%), and febrile neutropenia (n=3; 4%).
Three patients (4%) in the CVP±R arm had acute grade 3 neuropathy related to vincristine. Ten patients (14%) had grade 4 neutropenia.
The most common late toxicities for the entire patient cohort were salivary gland (n=8; 5%) and skin (n=4; 3%) toxicities.
Grade 3 lung and menopausal toxicities occurred in 1 patient each. Two patients had late grade 3 vincristine neuropathy. One patient who had grade 3 neuropathy during chemotherapy progressed to grade 4.
A multidrug regimen can improve upon involved-field radiotherapy (IFRT) in patients with early stage follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.
FL patients who received IFRT plus cyclophosphamide, vincristine, and prednisolone (CVP)—with or without rituximab—had a significant improvement in progression-free survival (PFS) compared to patients who received standard treatment with IFRT alone.
However, there was no significant difference in overall survival (OS) between the treatment arms.
“This is the first successful randomized study ever to be conducted in early stage follicular lymphoma comparing standard therapy to standard therapy plus effective chemotherapy or immunochemotherapy,” said Michael MacManus, MBBCh, of Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
“It shows that the initial treatment received by patients can significantly affect their long-term chance of staying free from disease. Moving forward, we are interested in determining whether there is a benefit in overall long-term survival for patients treated with the combination with further follow-up, and if there is any way to predict if a person will benefit from combined treatment based on analyses of blood or biopsy specimens.”
Dr MacManus and his colleagues studied 150 patients with stage I to II, low-grade FL who were enrolled in this trial between 2000 and 2012.
At randomization, the patients’ median age was 57, 52% were male, 75% had stage I disease, and 48% had PET staging.
Half of patients (n=75) were randomized to receive IFRT (30-36 Gy) alone, and half were randomized to IFRT (30-36 Gy) plus 6 cycles of CVP. From 2006 on, patients in the CVP arm received rituximab (R) as well (n=31).
Baseline characteristics were well-balanced between the treatment arms.
Efficacy
The median follow-up was 9.6 years (range, 3.1 to 15.8 years).
PFS was significantly better among patients randomized to receive CVP±R (hazard ratio [HR]=0.57; P=0.033). The estimated 10-year PFS rate was 41% in the IFRT arm and 59% in the CVP±R arm.
Patients randomized to receive CVP plus R (n=31) had significantly better PFS than patients randomized to receive IFRT alone (n=31) over the same time period (HR=0.26; P=0.045).
There were 10 deaths in the IRFT arm and 5 in the CVP±R arm, but there was no significant difference in OS between the arms (HR=0.62; P=0.40). The 10-year OS rate was 86% in the IFRT arm and 95% in the CVP±R arm.
There was no significant between-arm difference in transformation to aggressive lymphoma (P=0.1). Transformation occurred in 10 patients in the IFRT arm and 4 in the CVP±R arm.
Safety
There were 148 patients from both arms who ultimately received IFRT, and 69 patients who received CVP±R.
Grade 2 toxicities occurring in more than 10% of IFRT recipients included upper gastrointestinal (n=27; 18%), skin (n=21; 14%), and mucous membrane (n=19; 12%) toxicity. One IFRT recipient had grade 3 mucositis, and 1 had grade 4 esophageal/pharyngeal mucosal toxicity.
Grade 3 toxicities occurring in at least 2 patients in the CVP±R arm included neutropenia (n=10; 14%), infection (n=8; 12%), diarrhea (n=3; 4%), elevated gamma-glutamyl transferase (n=3; 4%), fatigue (n=3; 4%), and febrile neutropenia (n=3; 4%).
Three patients (4%) in the CVP±R arm had acute grade 3 neuropathy related to vincristine. Ten patients (14%) had grade 4 neutropenia.
The most common late toxicities for the entire patient cohort were salivary gland (n=8; 5%) and skin (n=4; 3%) toxicities.
Grade 3 lung and menopausal toxicities occurred in 1 patient each. Two patients had late grade 3 vincristine neuropathy. One patient who had grade 3 neuropathy during chemotherapy progressed to grade 4.
A multidrug regimen can improve upon involved-field radiotherapy (IFRT) in patients with early stage follicular lymphoma (FL), according to research published in the Journal of Clinical Oncology.
FL patients who received IFRT plus cyclophosphamide, vincristine, and prednisolone (CVP)—with or without rituximab—had a significant improvement in progression-free survival (PFS) compared to patients who received standard treatment with IFRT alone.
However, there was no significant difference in overall survival (OS) between the treatment arms.
“This is the first successful randomized study ever to be conducted in early stage follicular lymphoma comparing standard therapy to standard therapy plus effective chemotherapy or immunochemotherapy,” said Michael MacManus, MBBCh, of Peter MacCallum Cancer Centre in Melbourne, Victoria, Australia.
“It shows that the initial treatment received by patients can significantly affect their long-term chance of staying free from disease. Moving forward, we are interested in determining whether there is a benefit in overall long-term survival for patients treated with the combination with further follow-up, and if there is any way to predict if a person will benefit from combined treatment based on analyses of blood or biopsy specimens.”
Dr MacManus and his colleagues studied 150 patients with stage I to II, low-grade FL who were enrolled in this trial between 2000 and 2012.
At randomization, the patients’ median age was 57, 52% were male, 75% had stage I disease, and 48% had PET staging.
Half of patients (n=75) were randomized to receive IFRT (30-36 Gy) alone, and half were randomized to IFRT (30-36 Gy) plus 6 cycles of CVP. From 2006 on, patients in the CVP arm received rituximab (R) as well (n=31).
Baseline characteristics were well-balanced between the treatment arms.
Efficacy
The median follow-up was 9.6 years (range, 3.1 to 15.8 years).
PFS was significantly better among patients randomized to receive CVP±R (hazard ratio [HR]=0.57; P=0.033). The estimated 10-year PFS rate was 41% in the IFRT arm and 59% in the CVP±R arm.
Patients randomized to receive CVP plus R (n=31) had significantly better PFS than patients randomized to receive IFRT alone (n=31) over the same time period (HR=0.26; P=0.045).
There were 10 deaths in the IRFT arm and 5 in the CVP±R arm, but there was no significant difference in OS between the arms (HR=0.62; P=0.40). The 10-year OS rate was 86% in the IFRT arm and 95% in the CVP±R arm.
There was no significant between-arm difference in transformation to aggressive lymphoma (P=0.1). Transformation occurred in 10 patients in the IFRT arm and 4 in the CVP±R arm.
Safety
There were 148 patients from both arms who ultimately received IFRT, and 69 patients who received CVP±R.
Grade 2 toxicities occurring in more than 10% of IFRT recipients included upper gastrointestinal (n=27; 18%), skin (n=21; 14%), and mucous membrane (n=19; 12%) toxicity. One IFRT recipient had grade 3 mucositis, and 1 had grade 4 esophageal/pharyngeal mucosal toxicity.
Grade 3 toxicities occurring in at least 2 patients in the CVP±R arm included neutropenia (n=10; 14%), infection (n=8; 12%), diarrhea (n=3; 4%), elevated gamma-glutamyl transferase (n=3; 4%), fatigue (n=3; 4%), and febrile neutropenia (n=3; 4%).
Three patients (4%) in the CVP±R arm had acute grade 3 neuropathy related to vincristine. Ten patients (14%) had grade 4 neutropenia.
The most common late toxicities for the entire patient cohort were salivary gland (n=8; 5%) and skin (n=4; 3%) toxicities.
Grade 3 lung and menopausal toxicities occurred in 1 patient each. Two patients had late grade 3 vincristine neuropathy. One patient who had grade 3 neuropathy during chemotherapy progressed to grade 4.
Drug receives orphan designation for MM
The US Food and Drug Administration (FDA) has granted orphan drug designation to SRF231 for the treatment of multiple myeloma (MM).
SRF231 is a fully human antibody that inhibits the activity of CD47, a protein that is overexpressed on many cancer cells and prevents them from being engulfed and eliminated by macrophages.
Surface Oncology, the company developing SRF231, is currently conducting a phase 1 trial (NCT03512340) of SRF231 in patients with solid tumors and hematologic malignancies.
Preclinical research on SRF231 was presented at the 2016 ASH Annual Meeting.
SRF231 demonstrated “potent” activity against hematologic malignancies, according to researchers.
The team said SRF231 promoted macrophage-mediated phagocytic clearance of several hematologic primary tumor samples and cell lines in vitro.
SRF231 also demonstrated activity in murine xenograft models of hematologic malignancies. Specifically, the researchers observed “profound tumor growth inhibition” in models of MM, diffuse large B-cell lymphoma, and Burkitt lymphoma.
The team said SRF231 demonstrated activity when given alone or in combination with opsonizing antibodies.
Results also showed that SRF231 did not induce hemagglutination or phagocytosis of red blood cells in vitro.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to SRF231 for the treatment of multiple myeloma (MM).
SRF231 is a fully human antibody that inhibits the activity of CD47, a protein that is overexpressed on many cancer cells and prevents them from being engulfed and eliminated by macrophages.
Surface Oncology, the company developing SRF231, is currently conducting a phase 1 trial (NCT03512340) of SRF231 in patients with solid tumors and hematologic malignancies.
Preclinical research on SRF231 was presented at the 2016 ASH Annual Meeting.
SRF231 demonstrated “potent” activity against hematologic malignancies, according to researchers.
The team said SRF231 promoted macrophage-mediated phagocytic clearance of several hematologic primary tumor samples and cell lines in vitro.
SRF231 also demonstrated activity in murine xenograft models of hematologic malignancies. Specifically, the researchers observed “profound tumor growth inhibition” in models of MM, diffuse large B-cell lymphoma, and Burkitt lymphoma.
The team said SRF231 demonstrated activity when given alone or in combination with opsonizing antibodies.
Results also showed that SRF231 did not induce hemagglutination or phagocytosis of red blood cells in vitro.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The US Food and Drug Administration (FDA) has granted orphan drug designation to SRF231 for the treatment of multiple myeloma (MM).
SRF231 is a fully human antibody that inhibits the activity of CD47, a protein that is overexpressed on many cancer cells and prevents them from being engulfed and eliminated by macrophages.
Surface Oncology, the company developing SRF231, is currently conducting a phase 1 trial (NCT03512340) of SRF231 in patients with solid tumors and hematologic malignancies.
Preclinical research on SRF231 was presented at the 2016 ASH Annual Meeting.
SRF231 demonstrated “potent” activity against hematologic malignancies, according to researchers.
The team said SRF231 promoted macrophage-mediated phagocytic clearance of several hematologic primary tumor samples and cell lines in vitro.
SRF231 also demonstrated activity in murine xenograft models of hematologic malignancies. Specifically, the researchers observed “profound tumor growth inhibition” in models of MM, diffuse large B-cell lymphoma, and Burkitt lymphoma.
The team said SRF231 demonstrated activity when given alone or in combination with opsonizing antibodies.
Results also showed that SRF231 did not induce hemagglutination or phagocytosis of red blood cells in vitro.
About orphan designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
CHMP supports expanded approval for epoetin alfa products
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.
The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).
The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The EC usually makes a decision within 67 days of the CHMP’s recommendation.
Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:
- To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
- To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
- For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
- For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
- For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).
The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.
The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).
The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The EC usually makes a decision within 67 days of the CHMP’s recommendation.
Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:
- To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
- To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
- For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
- For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
- For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).
The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended a change to the terms of marketing authorization for 3 versions of epoetin alfa—Abseamed, Binocrit, and Epoetin alfa Hexal.
The CHMP is recommending that all 3 products be approved to treat symptomatic anemia (hemoglobin concentration of ≤ 10 g/dL) in adults with low- or intermediate-1-risk primary myelodysplastic syndromes who have low serum erythropoietin (< 200 mU/mL).
The CHMP’s recommendation will be reviewed by the European Commission (EC), which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The EC usually makes a decision within 67 days of the CHMP’s recommendation.
Abseamed, Binocrit, and Epoetin alfa Hexal are already EC-approved for the following indications:
- To treat symptomatic anemia associated with chronic renal failure in adults and children ages 1 to 18 on hemodialysis and adults on peritoneal dialysis
- To treat symptomatic anemia associated with chronic renal failure in adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anemia of renal origin accompanied by clinical symptoms in patients
- For adults receiving chemotherapy for solid tumors, malignant lymphoma, or multiple myeloma who are at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anemia at the start of chemotherapy) for the treatment of anemia and reduction of transfusion requirements
- For adults in a predonation program to increase the yield of autologous blood; treatment should only be given to patients with moderate anemia (hemoglobin concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units for females or 5 or more units for males)
- For non-iron-deficient adults set to undergo major elective orthopedic surgery who have a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions; use should be restricted to patients with moderate anemia (eg, hemoglobin concentration range between 10 to 13 g/dL or 6.2 to 8.1 mmol/L) who do not have an autologous predonation program available and with expected moderate blood loss (900 to 1800 mL).
The marketing authorization holders are Medice Arzneimittel Pütter GmbH & Co. KG for Abseamed, Sandoz GmbH for Binocrit, and Hexal AG for Epoetin alfa Hexal.
Drug receives fast track designation for WM
The US Food and Drug Administration (FDA) has granted fast track designation to zanubrutinib for the treatment of Waldenström’s macroglobulinemia (WM).
Zanubrutinib (BGB-3111) is a BTK inhibitor being developed by BeiGene to treat various B-cell malignancies.
BeiGene is preparing to submit to the FDA, in the first half of 2019, a new drug application seeking accelerated approval of zanubrutinib for patients with WM.
The application will be supported by results from a phase 1 study. Results from this trial were presented at the 14th International Conference on Malignant Lymphoma (14-ICML) last year.
Researchers are also evaluating zanubrutinib in phase 2 (NCT03332173) and phase 3 (NCT03053440) trials of WM patients. In the phase 3 trial, researchers are comparing zanubrutinib to the BTK inhibitor ibrutinib.
Phase 1 results
As of March 31, 2017, 48 WM patients were enrolled in the phase 1 study. Thirty-eight patients had relapsed/refractory disease, and 10 patients were treatment-naïve.
There was a dose-escalation phase and a dose-expansion phase. The dose-expansion phase included doses of 160 mg twice a day or 320 mg once a day.
The most common (>10%) adverse events, (AEs) of any attribution were petechiae/purpura/contusion (35%), upper respiratory tract infection (31%), constipation (25%), diarrhea (19%), epistaxis (19%), nausea (17%), cough (15%), anemia (15%), headache (15%), neutropenia (13%), and rash (13%).
Most of these events were grade 1 or 2 in severity. The exceptions were grade 3/4 anemia and neutropenia (8% each) as well as grade 3/4 diarrhea and headache (2% each).
Five serious AEs were considered possibly related to zanubrutinib—1 case each of hemothorax, atrial fibrillation, colitis, febrile neutropenia, and headache. Three AEs led to treatment discontinuation—1 case each of bronchiectasis, prostate adenocarcinoma, and adenocarcinoma of pylorus.
At the time of the data cutoff, 42 patients were evaluable for response. At a median follow-up of 12.3 months (range, 4.4 to 30.5 months), the overall response rate was 90% (38/42).
The major response rate was 76% (32/42), with very good partial responses in 43% (18/42) of patients and partial responses in 33% (14/42) of patients. There were no complete responses and 2 cases of disease progression.
About fast track designation
The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.
Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.
The US Food and Drug Administration (FDA) has granted fast track designation to zanubrutinib for the treatment of Waldenström’s macroglobulinemia (WM).
Zanubrutinib (BGB-3111) is a BTK inhibitor being developed by BeiGene to treat various B-cell malignancies.
BeiGene is preparing to submit to the FDA, in the first half of 2019, a new drug application seeking accelerated approval of zanubrutinib for patients with WM.
The application will be supported by results from a phase 1 study. Results from this trial were presented at the 14th International Conference on Malignant Lymphoma (14-ICML) last year.
Researchers are also evaluating zanubrutinib in phase 2 (NCT03332173) and phase 3 (NCT03053440) trials of WM patients. In the phase 3 trial, researchers are comparing zanubrutinib to the BTK inhibitor ibrutinib.
Phase 1 results
As of March 31, 2017, 48 WM patients were enrolled in the phase 1 study. Thirty-eight patients had relapsed/refractory disease, and 10 patients were treatment-naïve.
There was a dose-escalation phase and a dose-expansion phase. The dose-expansion phase included doses of 160 mg twice a day or 320 mg once a day.
The most common (>10%) adverse events, (AEs) of any attribution were petechiae/purpura/contusion (35%), upper respiratory tract infection (31%), constipation (25%), diarrhea (19%), epistaxis (19%), nausea (17%), cough (15%), anemia (15%), headache (15%), neutropenia (13%), and rash (13%).
Most of these events were grade 1 or 2 in severity. The exceptions were grade 3/4 anemia and neutropenia (8% each) as well as grade 3/4 diarrhea and headache (2% each).
Five serious AEs were considered possibly related to zanubrutinib—1 case each of hemothorax, atrial fibrillation, colitis, febrile neutropenia, and headache. Three AEs led to treatment discontinuation—1 case each of bronchiectasis, prostate adenocarcinoma, and adenocarcinoma of pylorus.
At the time of the data cutoff, 42 patients were evaluable for response. At a median follow-up of 12.3 months (range, 4.4 to 30.5 months), the overall response rate was 90% (38/42).
The major response rate was 76% (32/42), with very good partial responses in 43% (18/42) of patients and partial responses in 33% (14/42) of patients. There were no complete responses and 2 cases of disease progression.
About fast track designation
The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.
Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.
The US Food and Drug Administration (FDA) has granted fast track designation to zanubrutinib for the treatment of Waldenström’s macroglobulinemia (WM).
Zanubrutinib (BGB-3111) is a BTK inhibitor being developed by BeiGene to treat various B-cell malignancies.
BeiGene is preparing to submit to the FDA, in the first half of 2019, a new drug application seeking accelerated approval of zanubrutinib for patients with WM.
The application will be supported by results from a phase 1 study. Results from this trial were presented at the 14th International Conference on Malignant Lymphoma (14-ICML) last year.
Researchers are also evaluating zanubrutinib in phase 2 (NCT03332173) and phase 3 (NCT03053440) trials of WM patients. In the phase 3 trial, researchers are comparing zanubrutinib to the BTK inhibitor ibrutinib.
Phase 1 results
As of March 31, 2017, 48 WM patients were enrolled in the phase 1 study. Thirty-eight patients had relapsed/refractory disease, and 10 patients were treatment-naïve.
There was a dose-escalation phase and a dose-expansion phase. The dose-expansion phase included doses of 160 mg twice a day or 320 mg once a day.
The most common (>10%) adverse events, (AEs) of any attribution were petechiae/purpura/contusion (35%), upper respiratory tract infection (31%), constipation (25%), diarrhea (19%), epistaxis (19%), nausea (17%), cough (15%), anemia (15%), headache (15%), neutropenia (13%), and rash (13%).
Most of these events were grade 1 or 2 in severity. The exceptions were grade 3/4 anemia and neutropenia (8% each) as well as grade 3/4 diarrhea and headache (2% each).
Five serious AEs were considered possibly related to zanubrutinib—1 case each of hemothorax, atrial fibrillation, colitis, febrile neutropenia, and headache. Three AEs led to treatment discontinuation—1 case each of bronchiectasis, prostate adenocarcinoma, and adenocarcinoma of pylorus.
At the time of the data cutoff, 42 patients were evaluable for response. At a median follow-up of 12.3 months (range, 4.4 to 30.5 months), the overall response rate was 90% (38/42).
The major response rate was 76% (32/42), with very good partial responses in 43% (18/42) of patients and partial responses in 33% (14/42) of patients. There were no complete responses and 2 cases of disease progression.
About fast track designation
The FDA’s fast track development program is designed to expedite clinical development and submission of applications for products with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the product’s development plan and written communications about issues such as trial design and use of biomarkers.
Products that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Such products may also be eligible for rolling review, which allows a developer to submit individual sections of a product’s application for review as they are ready, rather than waiting until all sections are complete.
Rituximab reduces risk of follicular lymphoma transformation
Rituximab-based chemotherapy can significantly reduce the risk of transformation of follicular lymphoma (FL) from an indolent to an aggressive histology, such as diffuse large B-cell lymphoma, results of a retrospective pooled analysis have suggested.
“Despite the intrinsic limitations related to the retrospective nature of our study, we confirmed that the cumulative hazard of histological transformation as a first event in follicular lymphoma can be reduced significantly by introducing rituximab to a backbone therapy. Moreover, our data also confirm that histological transformation still has an adverse effect on patient outcome, although it is less catastrophic than the pre-rituximab regimens,” they wrote in the Lancet Haematology.
These investigators, from 11 cooperative groups or institutions across Europe, pooled data on patients aged 18 years and older who had a histologically confirmed diagnosis of grade 1, 2, or 3a FL between Jan. 2, 1997, and Dec. 20, 2013.
They defined histologic transformation as a biopsy-proven aggressive lymphoma that occurred as a first event after first-line therapy.
Data on a total of 8,116 patients were available for analysis; 509 of these patients had had histologic transformations. After a median follow-up of 87 months, the 10-year cumulative hazard for all patients was 7.7%. The 10-year cumulative hazard – one of two primary endpoints – was 5.2% for patients who had received any rituximab versus 8.7% for those who did not, which translated into a hazard ratio of 0.73 (P = .004).
Among patients who received rituximab during induction only, the 10-year cumulative hazard was 5.9%, and it was 3.6% among those who received rituximab during induction and maintenance phases of treatment. This difference translated into a HR of 0.55 (P = .003).
The benefit of rituximab induction and maintenance – compared with induction only – held up in a multivariate analysis controlling for age at diagnosis, sex, FLIPI (Follicular Lymphoma International Prognostic Index) score, active surveillance vs. treatment, and FL grade (HR, 0.55; P = .016).
There were 287 deaths among the 509 patients with transformation, resulting in a 10-year survival after transformation of 32%.
The 5-year survival after transformation was 38% for patients who were not exposed to rituximab, 42% for patients who received induction rituximab, and 43% for those who received both induction and maintenance rituximab, but the differences between the three groups were not statistically significant.
“More comprehensive knowledge of the biological risk factors for follicular lymphoma transformation and the molecular pathways involved is likely to help clinicians make more accurate prognostic assessments and also inform the potential usefulness of novel drugs for the treatment of follicular lymphoma,” the researchers wrote.
The study was funded by the European Lymphoma Institute and other research groups. The researchers reported having no financial disclosures.
SOURCE: Federico M et al. Lancet Haematol. 2018 Jul 4. doi: 10.1016/S2352-3026(18)30090-5.
Rituximab-based chemotherapy can significantly reduce the risk of transformation of follicular lymphoma (FL) from an indolent to an aggressive histology, such as diffuse large B-cell lymphoma, results of a retrospective pooled analysis have suggested.
“Despite the intrinsic limitations related to the retrospective nature of our study, we confirmed that the cumulative hazard of histological transformation as a first event in follicular lymphoma can be reduced significantly by introducing rituximab to a backbone therapy. Moreover, our data also confirm that histological transformation still has an adverse effect on patient outcome, although it is less catastrophic than the pre-rituximab regimens,” they wrote in the Lancet Haematology.
These investigators, from 11 cooperative groups or institutions across Europe, pooled data on patients aged 18 years and older who had a histologically confirmed diagnosis of grade 1, 2, or 3a FL between Jan. 2, 1997, and Dec. 20, 2013.
They defined histologic transformation as a biopsy-proven aggressive lymphoma that occurred as a first event after first-line therapy.
Data on a total of 8,116 patients were available for analysis; 509 of these patients had had histologic transformations. After a median follow-up of 87 months, the 10-year cumulative hazard for all patients was 7.7%. The 10-year cumulative hazard – one of two primary endpoints – was 5.2% for patients who had received any rituximab versus 8.7% for those who did not, which translated into a hazard ratio of 0.73 (P = .004).
Among patients who received rituximab during induction only, the 10-year cumulative hazard was 5.9%, and it was 3.6% among those who received rituximab during induction and maintenance phases of treatment. This difference translated into a HR of 0.55 (P = .003).
The benefit of rituximab induction and maintenance – compared with induction only – held up in a multivariate analysis controlling for age at diagnosis, sex, FLIPI (Follicular Lymphoma International Prognostic Index) score, active surveillance vs. treatment, and FL grade (HR, 0.55; P = .016).
There were 287 deaths among the 509 patients with transformation, resulting in a 10-year survival after transformation of 32%.
The 5-year survival after transformation was 38% for patients who were not exposed to rituximab, 42% for patients who received induction rituximab, and 43% for those who received both induction and maintenance rituximab, but the differences between the three groups were not statistically significant.
“More comprehensive knowledge of the biological risk factors for follicular lymphoma transformation and the molecular pathways involved is likely to help clinicians make more accurate prognostic assessments and also inform the potential usefulness of novel drugs for the treatment of follicular lymphoma,” the researchers wrote.
The study was funded by the European Lymphoma Institute and other research groups. The researchers reported having no financial disclosures.
SOURCE: Federico M et al. Lancet Haematol. 2018 Jul 4. doi: 10.1016/S2352-3026(18)30090-5.
Rituximab-based chemotherapy can significantly reduce the risk of transformation of follicular lymphoma (FL) from an indolent to an aggressive histology, such as diffuse large B-cell lymphoma, results of a retrospective pooled analysis have suggested.
“Despite the intrinsic limitations related to the retrospective nature of our study, we confirmed that the cumulative hazard of histological transformation as a first event in follicular lymphoma can be reduced significantly by introducing rituximab to a backbone therapy. Moreover, our data also confirm that histological transformation still has an adverse effect on patient outcome, although it is less catastrophic than the pre-rituximab regimens,” they wrote in the Lancet Haematology.
These investigators, from 11 cooperative groups or institutions across Europe, pooled data on patients aged 18 years and older who had a histologically confirmed diagnosis of grade 1, 2, or 3a FL between Jan. 2, 1997, and Dec. 20, 2013.
They defined histologic transformation as a biopsy-proven aggressive lymphoma that occurred as a first event after first-line therapy.
Data on a total of 8,116 patients were available for analysis; 509 of these patients had had histologic transformations. After a median follow-up of 87 months, the 10-year cumulative hazard for all patients was 7.7%. The 10-year cumulative hazard – one of two primary endpoints – was 5.2% for patients who had received any rituximab versus 8.7% for those who did not, which translated into a hazard ratio of 0.73 (P = .004).
Among patients who received rituximab during induction only, the 10-year cumulative hazard was 5.9%, and it was 3.6% among those who received rituximab during induction and maintenance phases of treatment. This difference translated into a HR of 0.55 (P = .003).
The benefit of rituximab induction and maintenance – compared with induction only – held up in a multivariate analysis controlling for age at diagnosis, sex, FLIPI (Follicular Lymphoma International Prognostic Index) score, active surveillance vs. treatment, and FL grade (HR, 0.55; P = .016).
There were 287 deaths among the 509 patients with transformation, resulting in a 10-year survival after transformation of 32%.
The 5-year survival after transformation was 38% for patients who were not exposed to rituximab, 42% for patients who received induction rituximab, and 43% for those who received both induction and maintenance rituximab, but the differences between the three groups were not statistically significant.
“More comprehensive knowledge of the biological risk factors for follicular lymphoma transformation and the molecular pathways involved is likely to help clinicians make more accurate prognostic assessments and also inform the potential usefulness of novel drugs for the treatment of follicular lymphoma,” the researchers wrote.
The study was funded by the European Lymphoma Institute and other research groups. The researchers reported having no financial disclosures.
SOURCE: Federico M et al. Lancet Haematol. 2018 Jul 4. doi: 10.1016/S2352-3026(18)30090-5.
FROM THE LANCET HAEMATOLOGY
Key clinical point:
Major finding: The 10-year cumulative hazard of histologic transformation was 5.2% for patients who had received rituximab and 8.7% for those who had not.
Study details: Retrospective pooled analysis of 8,116 patients with FL, 509 of whom had transformation over a 10-year period.
Disclosures: The study was funded by Associazione Angela Serra per la Ricerca sul Cancro, European Lymphoma Institute, European Hematology Association Lymphoma Group, Fondazione Italiana Linfomi, and the Spanish Group of Lymphoma and Bone Marrow Transplantation. The researchers reported having no financial disclosures.
Source: Federico M et al. Lancet Haematol. 2018 Jul 4. doi: 10.1016/S2352-3026(18)30090-5.
Ibrutinib stacks up well on safety in pooled analysis
in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL), according to findings from a pooled analysis.
Susan M. O’Brien, MD, of the University of California, Irvine, and her colleagues reported pooled data from four randomized, controlled trials that included a 756 patients treated with ibrutinib and 749 patients who received a comparator drug. Patients were treated for either CLL/SLL or MCL, and safety was assessed by comparing crude and exposure-adjusted incidence rates of reported adverse events (AEs).
The comparator drugs included intravenous ofatumumab, oral chlorambucil, intravenous bendamustine plus rituximab, and intravenous temsirolimus.
While adverse event data have been published for each study analyzed, the researchers noted that the pooled analysis allows for an “in-depth assessment of the frequency and severity of both common AEs as well as additional AEs of clinical interest.”
Ibrutinib-treated patients had low rates of treatment discontinuation, compared with comparator-treatment patients (27% vs. 85%), the researchers reported in Clinical Lymphoma, Myeloma & Leukemia. Most discontinuations were caused by disease progression.
In terms of AEs, the types of events reported were similar among the drugs, with the three most common being infections, gastrointestinal disorders, and general disorders/administration-site conditions.
Diarrhea, muscle spasms, and arthralgia were reported more often among ibrutinib-treated patients. The prevalence of the most common all-grade AEs generally decreased over time with ibrutinib, peaking in the first 3 months of treatment. For serious AEs, only atrial fibrillation was higher with ibrutinib than comparator drugs when adjusted for exposure.
SOURCE: O’Brien SM et al. Clin Lymphoma Myeloma Leuk. 2018 Jun 27. doi: 10.1016/j.clml.2018.06.016.
in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL), according to findings from a pooled analysis.
Susan M. O’Brien, MD, of the University of California, Irvine, and her colleagues reported pooled data from four randomized, controlled trials that included a 756 patients treated with ibrutinib and 749 patients who received a comparator drug. Patients were treated for either CLL/SLL or MCL, and safety was assessed by comparing crude and exposure-adjusted incidence rates of reported adverse events (AEs).
The comparator drugs included intravenous ofatumumab, oral chlorambucil, intravenous bendamustine plus rituximab, and intravenous temsirolimus.
While adverse event data have been published for each study analyzed, the researchers noted that the pooled analysis allows for an “in-depth assessment of the frequency and severity of both common AEs as well as additional AEs of clinical interest.”
Ibrutinib-treated patients had low rates of treatment discontinuation, compared with comparator-treatment patients (27% vs. 85%), the researchers reported in Clinical Lymphoma, Myeloma & Leukemia. Most discontinuations were caused by disease progression.
In terms of AEs, the types of events reported were similar among the drugs, with the three most common being infections, gastrointestinal disorders, and general disorders/administration-site conditions.
Diarrhea, muscle spasms, and arthralgia were reported more often among ibrutinib-treated patients. The prevalence of the most common all-grade AEs generally decreased over time with ibrutinib, peaking in the first 3 months of treatment. For serious AEs, only atrial fibrillation was higher with ibrutinib than comparator drugs when adjusted for exposure.
SOURCE: O’Brien SM et al. Clin Lymphoma Myeloma Leuk. 2018 Jun 27. doi: 10.1016/j.clml.2018.06.016.
in the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL), according to findings from a pooled analysis.
Susan M. O’Brien, MD, of the University of California, Irvine, and her colleagues reported pooled data from four randomized, controlled trials that included a 756 patients treated with ibrutinib and 749 patients who received a comparator drug. Patients were treated for either CLL/SLL or MCL, and safety was assessed by comparing crude and exposure-adjusted incidence rates of reported adverse events (AEs).
The comparator drugs included intravenous ofatumumab, oral chlorambucil, intravenous bendamustine plus rituximab, and intravenous temsirolimus.
While adverse event data have been published for each study analyzed, the researchers noted that the pooled analysis allows for an “in-depth assessment of the frequency and severity of both common AEs as well as additional AEs of clinical interest.”
Ibrutinib-treated patients had low rates of treatment discontinuation, compared with comparator-treatment patients (27% vs. 85%), the researchers reported in Clinical Lymphoma, Myeloma & Leukemia. Most discontinuations were caused by disease progression.
In terms of AEs, the types of events reported were similar among the drugs, with the three most common being infections, gastrointestinal disorders, and general disorders/administration-site conditions.
Diarrhea, muscle spasms, and arthralgia were reported more often among ibrutinib-treated patients. The prevalence of the most common all-grade AEs generally decreased over time with ibrutinib, peaking in the first 3 months of treatment. For serious AEs, only atrial fibrillation was higher with ibrutinib than comparator drugs when adjusted for exposure.
SOURCE: O’Brien SM et al. Clin Lymphoma Myeloma Leuk. 2018 Jun 27. doi: 10.1016/j.clml.2018.06.016.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
FDA grants UCB product orphan designation
The US Food and Drug Administration (FDA) has granted orphan drug designation to NiCord for hematopoietic stem cell transplant.
NiCord is created by expanding and enriching a unit of umbilical cord blood (UCB).
The product consists of a CD133-positive fraction—which is cultured for 21 days with nicotinamide, thrombopoietin, IL-6, FLT-3 ligand, and stem cell factor—and a CD133-negative fraction that is provided at the time of transplant.
NiCord already has orphan drug designation from the FDA as a treatment for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma, and myelodysplastic syndromes (MDS).
The product also has breakthrough therapy designation from the FDA.
NiCord trials
Final results from a phase 1/2 study suggested that NiCord can be used as a stand-alone graft in patients with high-risk hematologic malignancies. The results were presented at the 2018 BMT Tandem Meetings in February.
The trial included 36 adolescents and adults with AML (n=17), ALL (n=9), MDS (n=7), chronic myeloid leukemia (CML, n=2), and Hodgkin lymphoma (n=1).
All patients received a single NiCord unit. Researchers compared engraftment results in the NiCord recipients to results in a cohort of 148 patients from the CIBMTR registry.
The registry patients underwent standard UCB transplants and had similar characteristics as the NiCord recipients. However, only 20% of the CIBMTR patients received a single UCB unit.
The median time to neutrophil engraftment was 11.5 days (range, 6-26) with NiCord and 21 days in the control cohort (P<0.001). The cumulative incidence of neutrophil engraftment was 94.4% and 89.7%, respectively.
The median time to platelet engraftment was 34 days (range, 25-96) with NiCord and 46 days in the controls (P<0.001). The cumulative incidence of platelet engraftment was 80.6% and 67.1%, respectively.
There was 1 case of primary graft failure among the NiCord recipients and 2 cases of secondary graft failure.
The estimated 2-year rate of non-relapse mortality in NiCord recipients was 23.8%, and the 2-year incidence of relapse was 33.2%.
The estimated disease-free survival was 49.1% at 1 year and 43.0% at 2 years. The overall survival was 51.2% at 1 year and 2 years.
At 100 days, the rate of grade 2-4 acute graft-vs-host disease (GVHD) was 44.0%, and the rate of grade 3-4 acute GVHD was 11.1%. The estimated 1-year rate of mild to severe chronic GVHD was 40.5%, and the 2-year rate of moderate to severe chronic GVHD was 9.8%.
These results prompted a phase 3 study of NiCord in patients with AML, ALL, CML, MDS, and lymphoma (NCT02730299). In this trial, researchers are comparing NiCord to standard single or double UCB transplant.
About orphan and breakthrough designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted orphan drug designation to NiCord for hematopoietic stem cell transplant.
NiCord is created by expanding and enriching a unit of umbilical cord blood (UCB).
The product consists of a CD133-positive fraction—which is cultured for 21 days with nicotinamide, thrombopoietin, IL-6, FLT-3 ligand, and stem cell factor—and a CD133-negative fraction that is provided at the time of transplant.
NiCord already has orphan drug designation from the FDA as a treatment for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma, and myelodysplastic syndromes (MDS).
The product also has breakthrough therapy designation from the FDA.
NiCord trials
Final results from a phase 1/2 study suggested that NiCord can be used as a stand-alone graft in patients with high-risk hematologic malignancies. The results were presented at the 2018 BMT Tandem Meetings in February.
The trial included 36 adolescents and adults with AML (n=17), ALL (n=9), MDS (n=7), chronic myeloid leukemia (CML, n=2), and Hodgkin lymphoma (n=1).
All patients received a single NiCord unit. Researchers compared engraftment results in the NiCord recipients to results in a cohort of 148 patients from the CIBMTR registry.
The registry patients underwent standard UCB transplants and had similar characteristics as the NiCord recipients. However, only 20% of the CIBMTR patients received a single UCB unit.
The median time to neutrophil engraftment was 11.5 days (range, 6-26) with NiCord and 21 days in the control cohort (P<0.001). The cumulative incidence of neutrophil engraftment was 94.4% and 89.7%, respectively.
The median time to platelet engraftment was 34 days (range, 25-96) with NiCord and 46 days in the controls (P<0.001). The cumulative incidence of platelet engraftment was 80.6% and 67.1%, respectively.
There was 1 case of primary graft failure among the NiCord recipients and 2 cases of secondary graft failure.
The estimated 2-year rate of non-relapse mortality in NiCord recipients was 23.8%, and the 2-year incidence of relapse was 33.2%.
The estimated disease-free survival was 49.1% at 1 year and 43.0% at 2 years. The overall survival was 51.2% at 1 year and 2 years.
At 100 days, the rate of grade 2-4 acute graft-vs-host disease (GVHD) was 44.0%, and the rate of grade 3-4 acute GVHD was 11.1%. The estimated 1-year rate of mild to severe chronic GVHD was 40.5%, and the 2-year rate of moderate to severe chronic GVHD was 9.8%.
These results prompted a phase 3 study of NiCord in patients with AML, ALL, CML, MDS, and lymphoma (NCT02730299). In this trial, researchers are comparing NiCord to standard single or double UCB transplant.
About orphan and breakthrough designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
The US Food and Drug Administration (FDA) has granted orphan drug designation to NiCord for hematopoietic stem cell transplant.
NiCord is created by expanding and enriching a unit of umbilical cord blood (UCB).
The product consists of a CD133-positive fraction—which is cultured for 21 days with nicotinamide, thrombopoietin, IL-6, FLT-3 ligand, and stem cell factor—and a CD133-negative fraction that is provided at the time of transplant.
NiCord already has orphan drug designation from the FDA as a treatment for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin lymphoma, and myelodysplastic syndromes (MDS).
The product also has breakthrough therapy designation from the FDA.
NiCord trials
Final results from a phase 1/2 study suggested that NiCord can be used as a stand-alone graft in patients with high-risk hematologic malignancies. The results were presented at the 2018 BMT Tandem Meetings in February.
The trial included 36 adolescents and adults with AML (n=17), ALL (n=9), MDS (n=7), chronic myeloid leukemia (CML, n=2), and Hodgkin lymphoma (n=1).
All patients received a single NiCord unit. Researchers compared engraftment results in the NiCord recipients to results in a cohort of 148 patients from the CIBMTR registry.
The registry patients underwent standard UCB transplants and had similar characteristics as the NiCord recipients. However, only 20% of the CIBMTR patients received a single UCB unit.
The median time to neutrophil engraftment was 11.5 days (range, 6-26) with NiCord and 21 days in the control cohort (P<0.001). The cumulative incidence of neutrophil engraftment was 94.4% and 89.7%, respectively.
The median time to platelet engraftment was 34 days (range, 25-96) with NiCord and 46 days in the controls (P<0.001). The cumulative incidence of platelet engraftment was 80.6% and 67.1%, respectively.
There was 1 case of primary graft failure among the NiCord recipients and 2 cases of secondary graft failure.
The estimated 2-year rate of non-relapse mortality in NiCord recipients was 23.8%, and the 2-year incidence of relapse was 33.2%.
The estimated disease-free survival was 49.1% at 1 year and 43.0% at 2 years. The overall survival was 51.2% at 1 year and 2 years.
At 100 days, the rate of grade 2-4 acute graft-vs-host disease (GVHD) was 44.0%, and the rate of grade 3-4 acute GVHD was 11.1%. The estimated 1-year rate of mild to severe chronic GVHD was 40.5%, and the 2-year rate of moderate to severe chronic GVHD was 9.8%.
These results prompted a phase 3 study of NiCord in patients with AML, ALL, CML, MDS, and lymphoma (NCT02730299). In this trial, researchers are comparing NiCord to standard single or double UCB transplant.
About orphan and breakthrough designation
The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.
Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.
The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.
Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review.
To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.
PET-guided treatment didn’t improve outcomes
In the PETAL trial, treatment intensification based on results of an interim positron emission tomography (PET) scan did not improve survival outcomes for patients with aggressive lymphomas.
PET-positive patients did not benefit by switching from R-CHOP to a more intensive chemotherapy regimen.
PET-negative patients did not benefit from 2 additional cycles of rituximab after R-CHOP.
These results were published in the Journal of Clinical Oncology.
PETAL was a randomized trial of patients with newly diagnosed T- or B-cell lymphomas.
Patients received 2 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)—plus rituximab (R-CHOP) in CD20-positive lymphomas—followed by a PET scan.
PET-positive patients were randomized to receive 6 additional cycles of R-CHOP or 6 blocks of an intensive protocol used to treat Burkitt lymphoma. This protocol consisted of high-dose methotrexate, cytarabine, hyperfractionated cyclophosphamide and ifosfamide, split-dose doxorubicin and etoposide, vincristine, vindesine, and dexamethasone.
PET-negative patients with CD20-positive lymphomas were randomized to receive 4 additional cycles of R-CHOP or 4 additional cycles of R-CHOP followed by 2 more doses of rituximab.
Among patients with T-cell lymphomas, only PET-positive individuals underwent randomization. PET-negative patients received CHOP. Patients with CD20-positive T-cell lymphomas also received rituximab.
PET-positive results
Of the PET-positive patients (108/862), 52 were randomized to receive 6 additional cycles of R-CHOP, and 56 were randomized to 6 cycles of the Burkitt protocol.
In general, survival rates were similar regardless of treatment. The 2-year overall survival (OS) rate was 63.6% for patients who received R-CHOP and 55.4% for those who received the more intensive protocol.
Two-year progression-free survival (PFS) rates were 49.4% and 43.1%, respectively. Two-year event-free survival (EFS) rates were 42.0% and 31.6%, respectively.
Among patients with diffuse large B-cell lymphoma (DLBCL), the OS rate was 64.8% for patients who received R-CHOP and 47.1% for those on the Burkitt protocol. PFS rates were 55.5% and 41.4%, respectively.
There was a significant difference in EFS rates among the DLBCL patients—52.4% in the R-CHOP arm and 28.3% in the intensive arm (P=0.0186).
Among T-cell lymphoma patients, the OS rate was 22.2% in the R-CHOP arm and 30.0% in the intensive arm. The PFS rates were 12.7% and 30%, respectively. The EFS rates were the same as the PFS rates.
Overall, patients who received the Burkitt protocol had significantly higher rates of grade 3/4 hematologic toxicities, infection, and mucositis.
PET-negative results
Of 754 PET-negative patients, 697 had CD20-positive lymphomas, and 255 of those patients (all with B-cell lymphomas) underwent randomization.
There were 129 patients who were randomized to receive 6 cycles of R-CHOP (2 before and 4 after randomization) and 126 who were randomized to receive 6 cycles of R-CHOP plus 2 additional cycles of rituximab.
Again, survival rates were similar regardless of treatment.
The 2-year OS was 88.2% for patients who received only R-CHOP and 87.2% for those with additional rituximab exposure. PFS rates were 82.0% and 77.5%, respectively. EFS rates were 76.4% and 73.5%, respectively.
In the DLBCL patients, the OS rate was 88.5% in the R-CHOP arm and 85.8% in the intensive arm. PFS rates were 82.3% and 77.7%, respectively. EFS rates were 72.6% and 78.9%, respectively.
As increasing the dose of rituximab did not improve outcomes, the investigators concluded that 6 cycles of R-CHOP should be the standard of care for these patients.
The team also said interim PET scanning is “a powerful tool” for identifying chemotherapy-resistant lymphomas, and PET-positive patients may be candidates for immunologic treatment approaches.
In the PETAL trial, treatment intensification based on results of an interim positron emission tomography (PET) scan did not improve survival outcomes for patients with aggressive lymphomas.
PET-positive patients did not benefit by switching from R-CHOP to a more intensive chemotherapy regimen.
PET-negative patients did not benefit from 2 additional cycles of rituximab after R-CHOP.
These results were published in the Journal of Clinical Oncology.
PETAL was a randomized trial of patients with newly diagnosed T- or B-cell lymphomas.
Patients received 2 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)—plus rituximab (R-CHOP) in CD20-positive lymphomas—followed by a PET scan.
PET-positive patients were randomized to receive 6 additional cycles of R-CHOP or 6 blocks of an intensive protocol used to treat Burkitt lymphoma. This protocol consisted of high-dose methotrexate, cytarabine, hyperfractionated cyclophosphamide and ifosfamide, split-dose doxorubicin and etoposide, vincristine, vindesine, and dexamethasone.
PET-negative patients with CD20-positive lymphomas were randomized to receive 4 additional cycles of R-CHOP or 4 additional cycles of R-CHOP followed by 2 more doses of rituximab.
Among patients with T-cell lymphomas, only PET-positive individuals underwent randomization. PET-negative patients received CHOP. Patients with CD20-positive T-cell lymphomas also received rituximab.
PET-positive results
Of the PET-positive patients (108/862), 52 were randomized to receive 6 additional cycles of R-CHOP, and 56 were randomized to 6 cycles of the Burkitt protocol.
In general, survival rates were similar regardless of treatment. The 2-year overall survival (OS) rate was 63.6% for patients who received R-CHOP and 55.4% for those who received the more intensive protocol.
Two-year progression-free survival (PFS) rates were 49.4% and 43.1%, respectively. Two-year event-free survival (EFS) rates were 42.0% and 31.6%, respectively.
Among patients with diffuse large B-cell lymphoma (DLBCL), the OS rate was 64.8% for patients who received R-CHOP and 47.1% for those on the Burkitt protocol. PFS rates were 55.5% and 41.4%, respectively.
There was a significant difference in EFS rates among the DLBCL patients—52.4% in the R-CHOP arm and 28.3% in the intensive arm (P=0.0186).
Among T-cell lymphoma patients, the OS rate was 22.2% in the R-CHOP arm and 30.0% in the intensive arm. The PFS rates were 12.7% and 30%, respectively. The EFS rates were the same as the PFS rates.
Overall, patients who received the Burkitt protocol had significantly higher rates of grade 3/4 hematologic toxicities, infection, and mucositis.
PET-negative results
Of 754 PET-negative patients, 697 had CD20-positive lymphomas, and 255 of those patients (all with B-cell lymphomas) underwent randomization.
There were 129 patients who were randomized to receive 6 cycles of R-CHOP (2 before and 4 after randomization) and 126 who were randomized to receive 6 cycles of R-CHOP plus 2 additional cycles of rituximab.
Again, survival rates were similar regardless of treatment.
The 2-year OS was 88.2% for patients who received only R-CHOP and 87.2% for those with additional rituximab exposure. PFS rates were 82.0% and 77.5%, respectively. EFS rates were 76.4% and 73.5%, respectively.
In the DLBCL patients, the OS rate was 88.5% in the R-CHOP arm and 85.8% in the intensive arm. PFS rates were 82.3% and 77.7%, respectively. EFS rates were 72.6% and 78.9%, respectively.
As increasing the dose of rituximab did not improve outcomes, the investigators concluded that 6 cycles of R-CHOP should be the standard of care for these patients.
The team also said interim PET scanning is “a powerful tool” for identifying chemotherapy-resistant lymphomas, and PET-positive patients may be candidates for immunologic treatment approaches.
In the PETAL trial, treatment intensification based on results of an interim positron emission tomography (PET) scan did not improve survival outcomes for patients with aggressive lymphomas.
PET-positive patients did not benefit by switching from R-CHOP to a more intensive chemotherapy regimen.
PET-negative patients did not benefit from 2 additional cycles of rituximab after R-CHOP.
These results were published in the Journal of Clinical Oncology.
PETAL was a randomized trial of patients with newly diagnosed T- or B-cell lymphomas.
Patients received 2 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)—plus rituximab (R-CHOP) in CD20-positive lymphomas—followed by a PET scan.
PET-positive patients were randomized to receive 6 additional cycles of R-CHOP or 6 blocks of an intensive protocol used to treat Burkitt lymphoma. This protocol consisted of high-dose methotrexate, cytarabine, hyperfractionated cyclophosphamide and ifosfamide, split-dose doxorubicin and etoposide, vincristine, vindesine, and dexamethasone.
PET-negative patients with CD20-positive lymphomas were randomized to receive 4 additional cycles of R-CHOP or 4 additional cycles of R-CHOP followed by 2 more doses of rituximab.
Among patients with T-cell lymphomas, only PET-positive individuals underwent randomization. PET-negative patients received CHOP. Patients with CD20-positive T-cell lymphomas also received rituximab.
PET-positive results
Of the PET-positive patients (108/862), 52 were randomized to receive 6 additional cycles of R-CHOP, and 56 were randomized to 6 cycles of the Burkitt protocol.
In general, survival rates were similar regardless of treatment. The 2-year overall survival (OS) rate was 63.6% for patients who received R-CHOP and 55.4% for those who received the more intensive protocol.
Two-year progression-free survival (PFS) rates were 49.4% and 43.1%, respectively. Two-year event-free survival (EFS) rates were 42.0% and 31.6%, respectively.
Among patients with diffuse large B-cell lymphoma (DLBCL), the OS rate was 64.8% for patients who received R-CHOP and 47.1% for those on the Burkitt protocol. PFS rates were 55.5% and 41.4%, respectively.
There was a significant difference in EFS rates among the DLBCL patients—52.4% in the R-CHOP arm and 28.3% in the intensive arm (P=0.0186).
Among T-cell lymphoma patients, the OS rate was 22.2% in the R-CHOP arm and 30.0% in the intensive arm. The PFS rates were 12.7% and 30%, respectively. The EFS rates were the same as the PFS rates.
Overall, patients who received the Burkitt protocol had significantly higher rates of grade 3/4 hematologic toxicities, infection, and mucositis.
PET-negative results
Of 754 PET-negative patients, 697 had CD20-positive lymphomas, and 255 of those patients (all with B-cell lymphomas) underwent randomization.
There were 129 patients who were randomized to receive 6 cycles of R-CHOP (2 before and 4 after randomization) and 126 who were randomized to receive 6 cycles of R-CHOP plus 2 additional cycles of rituximab.
Again, survival rates were similar regardless of treatment.
The 2-year OS was 88.2% for patients who received only R-CHOP and 87.2% for those with additional rituximab exposure. PFS rates were 82.0% and 77.5%, respectively. EFS rates were 76.4% and 73.5%, respectively.
In the DLBCL patients, the OS rate was 88.5% in the R-CHOP arm and 85.8% in the intensive arm. PFS rates were 82.3% and 77.7%, respectively. EFS rates were 72.6% and 78.9%, respectively.
As increasing the dose of rituximab did not improve outcomes, the investigators concluded that 6 cycles of R-CHOP should be the standard of care for these patients.
The team also said interim PET scanning is “a powerful tool” for identifying chemotherapy-resistant lymphomas, and PET-positive patients may be candidates for immunologic treatment approaches.