Follicular Lymphoma

The combination of lenalidomide and rituximab was more active in patients with recurrent follicular lymphoma, compared with lenalidomide alone, and significantly increased the overall response rate, according to new data published online Aug. 24 in the Journal of Clinical Oncology.

Although both lenalidomide and rituximab are active agents in follicular lymphoma, their combined use in recurrent follicular lymphoma has not been previously evaluated in randomized clinical trials, said Dr. John P. Leonard of Cornell University, New York, and his colleagues.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

The overall response rate of patients receiving the combination regimen was significantly higher than that of patients who received lenalidomide alone (P = .029). In the cohort receiving lenalidomide alone, 24 patients (53%) achieved an objective response (9 complete responses [20%]), while 35 patients (76%) in the lenalidomide/rituximab group were responders (18 complete responses [39%]).

At a median follow-up of 2.5 years (range, 0.1-4.8 years), the addition of rituximab to lenalidomide in this population also significantly increased the median time to progression: 1.1 year for lenalidomide alone versus 2 years for the combined therapy (P = .002).

Overall survival was 4.5 years for lenalidomide alone and has not yet been reached for the combination arm (P = .149.

This trial helps to establish the safety profile of single-agent lenalidomide in follicular lymphoma, while its “randomized nature also allows a direct assessment of potential toxicity resulting from the addition of rituximab to lenalidomide,” wrote Dr. Leonard and his associates (J Clin Oncol. 2015 Aug 24. doi: 10.1200/JCO.2014.59.9258).

“There was no evidence of increased toxicity from the lenalidomide/rituximab combination compared with lenalidomide alone,” they pointed out.

Both lenalidomide alone and lenalidomide/rituximab were well tolerated, with grade 3-4 adverse events occurring in 58% and 53% of patients, respectively, with 9% and 11% of patients experiencing grade 4 toxicity, respectively. The most common grade 3-4 adverse events included neutropenia (16% vs. 20%), fatigue (9% vs. 13%), and rash (4% vs. 4%).

The study was supported in part by grants from the National Cancer Institute to the Alliance for Clinical Trials in Oncology. Dr. Leonard reported financial relationships with Celgene and Genentech, and several coauthors also reported relationships with industry.

The combination of lenalidomide and rituximab was more active in patients with recurrent follicular lymphoma, compared with lenalidomide alone, and significantly increased the overall response rate, according to new data published online Aug. 24 in the Journal of Clinical Oncology.

Although both lenalidomide and rituximab are active agents in follicular lymphoma, their combined use in recurrent follicular lymphoma has not been previously evaluated in randomized clinical trials, said Dr. John P. Leonard of Cornell University, New York, and his colleagues.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

The overall response rate of patients receiving the combination regimen was significantly higher than that of patients who received lenalidomide alone (P = .029). In the cohort receiving lenalidomide alone, 24 patients (53%) achieved an objective response (9 complete responses [20%]), while 35 patients (76%) in the lenalidomide/rituximab group were responders (18 complete responses [39%]).

At a median follow-up of 2.5 years (range, 0.1-4.8 years), the addition of rituximab to lenalidomide in this population also significantly increased the median time to progression: 1.1 year for lenalidomide alone versus 2 years for the combined therapy (P = .002).

Overall survival was 4.5 years for lenalidomide alone and has not yet been reached for the combination arm (P = .149.

This trial helps to establish the safety profile of single-agent lenalidomide in follicular lymphoma, while its “randomized nature also allows a direct assessment of potential toxicity resulting from the addition of rituximab to lenalidomide,” wrote Dr. Leonard and his associates (J Clin Oncol. 2015 Aug 24. doi: 10.1200/JCO.2014.59.9258).

“There was no evidence of increased toxicity from the lenalidomide/rituximab combination compared with lenalidomide alone,” they pointed out.

Both lenalidomide alone and lenalidomide/rituximab were well tolerated, with grade 3-4 adverse events occurring in 58% and 53% of patients, respectively, with 9% and 11% of patients experiencing grade 4 toxicity, respectively. The most common grade 3-4 adverse events included neutropenia (16% vs. 20%), fatigue (9% vs. 13%), and rash (4% vs. 4%).

The study was supported in part by grants from the National Cancer Institute to the Alliance for Clinical Trials in Oncology. Dr. Leonard reported financial relationships with Celgene and Genentech, and several coauthors also reported relationships with industry.

The combination of lenalidomide and rituximab was more active in patients with recurrent follicular lymphoma, compared with lenalidomide alone, and significantly increased the overall response rate, according to new data published online Aug. 24 in the Journal of Clinical Oncology.

Although both lenalidomide and rituximab are active agents in follicular lymphoma, their combined use in recurrent follicular lymphoma has not been previously evaluated in randomized clinical trials, said Dr. John P. Leonard of Cornell University, New York, and his colleagues.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

The overall response rate of patients receiving the combination regimen was significantly higher than that of patients who received lenalidomide alone (P = .029). In the cohort receiving lenalidomide alone, 24 patients (53%) achieved an objective response (9 complete responses [20%]), while 35 patients (76%) in the lenalidomide/rituximab group were responders (18 complete responses [39%]).

At a median follow-up of 2.5 years (range, 0.1-4.8 years), the addition of rituximab to lenalidomide in this population also significantly increased the median time to progression: 1.1 year for lenalidomide alone versus 2 years for the combined therapy (P = .002).

Overall survival was 4.5 years for lenalidomide alone and has not yet been reached for the combination arm (P = .149.

This trial helps to establish the safety profile of single-agent lenalidomide in follicular lymphoma, while its “randomized nature also allows a direct assessment of potential toxicity resulting from the addition of rituximab to lenalidomide,” wrote Dr. Leonard and his associates (J Clin Oncol. 2015 Aug 24. doi: 10.1200/JCO.2014.59.9258).

“There was no evidence of increased toxicity from the lenalidomide/rituximab combination compared with lenalidomide alone,” they pointed out.

Both lenalidomide alone and lenalidomide/rituximab were well tolerated, with grade 3-4 adverse events occurring in 58% and 53% of patients, respectively, with 9% and 11% of patients experiencing grade 4 toxicity, respectively. The most common grade 3-4 adverse events included neutropenia (16% vs. 20%), fatigue (9% vs. 13%), and rash (4% vs. 4%).

The study was supported in part by grants from the National Cancer Institute to the Alliance for Clinical Trials in Oncology. Dr. Leonard reported financial relationships with Celgene and Genentech, and several coauthors also reported relationships with industry.

 

 

Doctor and patient

Photo courtesy of NIH

 

A newly developed prognostic model can identify follicular lymphoma (FL) patients at the highest risk for treatment failure, according to researchers.

To create this model, called m7-FLIPI, the team combined the Follicular Lymphoma International Prognostic Index (FLIPI), Eastern Cooperative Oncology Group (ECOG) performance status, and the mutation status of 7 genes—EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11.

The researchers said this is the first prognostic model for FL that accounts for both clinical factors and genetic mutations.

They described the creation and testing of the model in The Lancet Oncology.

“We set out to determine, at the time of diagnosis, which patients’ disease will have sustained responses after treatment and whether new genetic data could help inform which patients are at risk for developing progressive lymphoma so clinicians would be able to offer these high-risk patients more effective therapies,” said Randy Gascoyne, MD, of the British Columbia Cancer Agency in Vancouver, Canada.

He and his colleagues created the m7-FLIPI by conducting a retrospective analysis of genetic mutations and clinical risk factors in 2 cohorts of patients with symptomatic, advanced stage, or bulky FL grade 1, 2, or 3A.

The patients had a biopsy specimen collected 12 months or less before they began first-line treatment with an immunochemotherapy regimen containing rituximab.

Training cohort

The training cohort consisted of 151 FL patients who received R-CHOP. The median follow-up for these patients was 7.7 years.

When the researchers applied the m7-FLIPI to this cohort, they found 28% of patients (43/151) were defined as high-risk, with a 5-year failure-free survival (FFS) rate of 38.29%.

And 72% of patients (108/151) were defined as low-risk, with a 5-year FFS of 77.21%. The hazard ratio was 4.14 (P<0.0001).

The positive predictive value for 5-year FFS was 64%, and the negative predictive value was 78%. The m7-FLIPI outperformed a prognostic model of only gene mutations and the FLIPI-2.

Validation cohort

The validation cohort consisted of 107 patients who received R-CVP. The median follow-up for these patients was 6.7 years.

When the researchers applied the m7-FLIPI to this cohort, they found that 22% of patients (24/107) were defined as high-risk, with a 5-year FFS of 25%.

And 78% of patients (83/107) were defined as low-risk, with a 5-year FFS of 68.24%. The hazard ratio was 3.58 (P<0.0001).

The positive predictive value for 5-year FFS was 72%, and the negative predictive value was 68%. The m7-FLIPI outperformed the FLIPI alone and the FLIPI combined with ECOG performance status.

Overall survival

Although the m7-FLIPI was designed specifically for FFS, the researchers also tested its prognostic utility for overall survival (OS).

In the training cohort, high-risk disease according to the m7-FLIPI was associated with a 5-year OS of 65.25%, compared to 89.98% for low-risk disease (P=0.00031).

In the validation cohort, 5-year OS was 41.67% for patients with high-risk disease and 84.01% for patients with low-risk disease (P<0.0001). In both cohorts, the m7-FLIPI outperformed the FLIPI alone.

Based on these results, the researchers believe the m7-FLIPI could be utilized in a clinical setting to test all new FL patients at diagnosis and identify patients who harbor the most aggressive disease.

“The m7-FLIPI could be extremely significant for the medical community,” Dr Gascoyne said, “changing the story for high-risk patients who are currently destined to not respond well to standard treatment.”

 

 

Doctor and patient

Photo courtesy of NIH

 

A newly developed prognostic model can identify follicular lymphoma (FL) patients at the highest risk for treatment failure, according to researchers.

To create this model, called m7-FLIPI, the team combined the Follicular Lymphoma International Prognostic Index (FLIPI), Eastern Cooperative Oncology Group (ECOG) performance status, and the mutation status of 7 genes—EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11.

The researchers said this is the first prognostic model for FL that accounts for both clinical factors and genetic mutations.

They described the creation and testing of the model in The Lancet Oncology.

“We set out to determine, at the time of diagnosis, which patients’ disease will have sustained responses after treatment and whether new genetic data could help inform which patients are at risk for developing progressive lymphoma so clinicians would be able to offer these high-risk patients more effective therapies,” said Randy Gascoyne, MD, of the British Columbia Cancer Agency in Vancouver, Canada.

He and his colleagues created the m7-FLIPI by conducting a retrospective analysis of genetic mutations and clinical risk factors in 2 cohorts of patients with symptomatic, advanced stage, or bulky FL grade 1, 2, or 3A.

The patients had a biopsy specimen collected 12 months or less before they began first-line treatment with an immunochemotherapy regimen containing rituximab.

Training cohort

The training cohort consisted of 151 FL patients who received R-CHOP. The median follow-up for these patients was 7.7 years.

When the researchers applied the m7-FLIPI to this cohort, they found 28% of patients (43/151) were defined as high-risk, with a 5-year failure-free survival (FFS) rate of 38.29%.

And 72% of patients (108/151) were defined as low-risk, with a 5-year FFS of 77.21%. The hazard ratio was 4.14 (P<0.0001).

The positive predictive value for 5-year FFS was 64%, and the negative predictive value was 78%. The m7-FLIPI outperformed a prognostic model of only gene mutations and the FLIPI-2.

Validation cohort

The validation cohort consisted of 107 patients who received R-CVP. The median follow-up for these patients was 6.7 years.

When the researchers applied the m7-FLIPI to this cohort, they found that 22% of patients (24/107) were defined as high-risk, with a 5-year FFS of 25%.

And 78% of patients (83/107) were defined as low-risk, with a 5-year FFS of 68.24%. The hazard ratio was 3.58 (P<0.0001).

The positive predictive value for 5-year FFS was 72%, and the negative predictive value was 68%. The m7-FLIPI outperformed the FLIPI alone and the FLIPI combined with ECOG performance status.

Overall survival

Although the m7-FLIPI was designed specifically for FFS, the researchers also tested its prognostic utility for overall survival (OS).

In the training cohort, high-risk disease according to the m7-FLIPI was associated with a 5-year OS of 65.25%, compared to 89.98% for low-risk disease (P=0.00031).

In the validation cohort, 5-year OS was 41.67% for patients with high-risk disease and 84.01% for patients with low-risk disease (P<0.0001). In both cohorts, the m7-FLIPI outperformed the FLIPI alone.

Based on these results, the researchers believe the m7-FLIPI could be utilized in a clinical setting to test all new FL patients at diagnosis and identify patients who harbor the most aggressive disease.

“The m7-FLIPI could be extremely significant for the medical community,” Dr Gascoyne said, “changing the story for high-risk patients who are currently destined to not respond well to standard treatment.”

 

 

Doctor and patient

Photo courtesy of NIH

 

A newly developed prognostic model can identify follicular lymphoma (FL) patients at the highest risk for treatment failure, according to researchers.

To create this model, called m7-FLIPI, the team combined the Follicular Lymphoma International Prognostic Index (FLIPI), Eastern Cooperative Oncology Group (ECOG) performance status, and the mutation status of 7 genes—EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11.

The researchers said this is the first prognostic model for FL that accounts for both clinical factors and genetic mutations.

They described the creation and testing of the model in The Lancet Oncology.

“We set out to determine, at the time of diagnosis, which patients’ disease will have sustained responses after treatment and whether new genetic data could help inform which patients are at risk for developing progressive lymphoma so clinicians would be able to offer these high-risk patients more effective therapies,” said Randy Gascoyne, MD, of the British Columbia Cancer Agency in Vancouver, Canada.

He and his colleagues created the m7-FLIPI by conducting a retrospective analysis of genetic mutations and clinical risk factors in 2 cohorts of patients with symptomatic, advanced stage, or bulky FL grade 1, 2, or 3A.

The patients had a biopsy specimen collected 12 months or less before they began first-line treatment with an immunochemotherapy regimen containing rituximab.

Training cohort

The training cohort consisted of 151 FL patients who received R-CHOP. The median follow-up for these patients was 7.7 years.

When the researchers applied the m7-FLIPI to this cohort, they found 28% of patients (43/151) were defined as high-risk, with a 5-year failure-free survival (FFS) rate of 38.29%.

And 72% of patients (108/151) were defined as low-risk, with a 5-year FFS of 77.21%. The hazard ratio was 4.14 (P<0.0001).

The positive predictive value for 5-year FFS was 64%, and the negative predictive value was 78%. The m7-FLIPI outperformed a prognostic model of only gene mutations and the FLIPI-2.

Validation cohort

The validation cohort consisted of 107 patients who received R-CVP. The median follow-up for these patients was 6.7 years.

When the researchers applied the m7-FLIPI to this cohort, they found that 22% of patients (24/107) were defined as high-risk, with a 5-year FFS of 25%.

And 78% of patients (83/107) were defined as low-risk, with a 5-year FFS of 68.24%. The hazard ratio was 3.58 (P<0.0001).

The positive predictive value for 5-year FFS was 72%, and the negative predictive value was 68%. The m7-FLIPI outperformed the FLIPI alone and the FLIPI combined with ECOG performance status.

Overall survival

Although the m7-FLIPI was designed specifically for FFS, the researchers also tested its prognostic utility for overall survival (OS).

In the training cohort, high-risk disease according to the m7-FLIPI was associated with a 5-year OS of 65.25%, compared to 89.98% for low-risk disease (P=0.00031).

In the validation cohort, 5-year OS was 41.67% for patients with high-risk disease and 84.01% for patients with low-risk disease (P<0.0001). In both cohorts, the m7-FLIPI outperformed the FLIPI alone.

Based on these results, the researchers believe the m7-FLIPI could be utilized in a clinical setting to test all new FL patients at diagnosis and identify patients who harbor the most aggressive disease.

“The m7-FLIPI could be extremely significant for the medical community,” Dr Gascoyne said, “changing the story for high-risk patients who are currently destined to not respond well to standard treatment.”

For patients with follicular lymphoma treated with a rituximab-based combination chemotherapy regimen, early disease progression is associated with significantly worse overall survival, suggesting the need for additional interventions, according to results of a multicenter study.

Among 588 patients with stage 2-4 follicular lymphoma treated with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and followed for a median of 7 years in the National LymphoCare Study, overall survival (OS) at 2 years was 68% for those who had disease progression within 2 years, compared with 97% for patients with no disease progression during that time.

Similarly, 5-year overall survival was 50% for patients with early progression of disease, compared with 90% for patients with no early progression, write Dr. Carla Casulo of the University of Rochester (N.Y.) Medical Center and colleagues. The study is in anearly online publication in the Journal of Clinical Oncology.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

“Given our findings, early relapse after diagnosis in patients treated with first-line chemoimmunotherapy is a powerful prognostic indicator of outcome and should be used to stratify the risk of patients in studies of relapsed follicular lymphoma,” the authors wrote.

The findings were validated in an independent cohort of patients with follicular lymphoma treated with R-CHOP from the University of Iowa and Mayo Clinical Molecular Epidemiology Resource, and are consistent with findings from other studies of patients treated with different rituximab-based regimens, the investigators reported.

In unadjusted analysis, early disease progression was associated with a hazard ratio (HR) of 7.17 (95% confidence interval [CI] 4.83-10.65); the effect remained after adjustment for the Follicular Lymphoma International Prognostic Index (FLIPI) score (HR 6.44, 95% CI, 4.33-9.58).

Factors associated with early progression included age, Eastern Cooperative Oncology Group performance score, nodal sites, and disease stage.

Early use of aggressive salvage therapies or autologous stem-cell transplantation could improve outcomes in patients with early disease progression, the authors wrote. However, only 8 patients among the 110 with early progression went on to transplant, not a large enough sample for meaningful analysis, they added.

“This newly defined high-risk group of patients represents a distinct population in whom further study is warranted in both directed prospective clinical trials of follicular lymphoma biology and treatment. Moreover, we propose that 2-year progression-free survival may be a practical and meaningful clinical end point for trials involving a chemoimmunotherapy backbone,” they concluded.

For patients with follicular lymphoma treated with a rituximab-based combination chemotherapy regimen, early disease progression is associated with significantly worse overall survival, suggesting the need for additional interventions, according to results of a multicenter study.

Among 588 patients with stage 2-4 follicular lymphoma treated with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and followed for a median of 7 years in the National LymphoCare Study, overall survival (OS) at 2 years was 68% for those who had disease progression within 2 years, compared with 97% for patients with no disease progression during that time.

Similarly, 5-year overall survival was 50% for patients with early progression of disease, compared with 90% for patients with no early progression, write Dr. Carla Casulo of the University of Rochester (N.Y.) Medical Center and colleagues. The study is in anearly online publication in the Journal of Clinical Oncology.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

“Given our findings, early relapse after diagnosis in patients treated with first-line chemoimmunotherapy is a powerful prognostic indicator of outcome and should be used to stratify the risk of patients in studies of relapsed follicular lymphoma,” the authors wrote.

The findings were validated in an independent cohort of patients with follicular lymphoma treated with R-CHOP from the University of Iowa and Mayo Clinical Molecular Epidemiology Resource, and are consistent with findings from other studies of patients treated with different rituximab-based regimens, the investigators reported.

In unadjusted analysis, early disease progression was associated with a hazard ratio (HR) of 7.17 (95% confidence interval [CI] 4.83-10.65); the effect remained after adjustment for the Follicular Lymphoma International Prognostic Index (FLIPI) score (HR 6.44, 95% CI, 4.33-9.58).

Factors associated with early progression included age, Eastern Cooperative Oncology Group performance score, nodal sites, and disease stage.

Early use of aggressive salvage therapies or autologous stem-cell transplantation could improve outcomes in patients with early disease progression, the authors wrote. However, only 8 patients among the 110 with early progression went on to transplant, not a large enough sample for meaningful analysis, they added.

“This newly defined high-risk group of patients represents a distinct population in whom further study is warranted in both directed prospective clinical trials of follicular lymphoma biology and treatment. Moreover, we propose that 2-year progression-free survival may be a practical and meaningful clinical end point for trials involving a chemoimmunotherapy backbone,” they concluded.

For patients with follicular lymphoma treated with a rituximab-based combination chemotherapy regimen, early disease progression is associated with significantly worse overall survival, suggesting the need for additional interventions, according to results of a multicenter study.

Among 588 patients with stage 2-4 follicular lymphoma treated with first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) and followed for a median of 7 years in the National LymphoCare Study, overall survival (OS) at 2 years was 68% for those who had disease progression within 2 years, compared with 97% for patients with no disease progression during that time.

Similarly, 5-year overall survival was 50% for patients with early progression of disease, compared with 90% for patients with no early progression, write Dr. Carla Casulo of the University of Rochester (N.Y.) Medical Center and colleagues. The study is in anearly online publication in the Journal of Clinical Oncology.

Courtesy Wikimedia Commons/Ed Uthman/Creative Commons License

“Given our findings, early relapse after diagnosis in patients treated with first-line chemoimmunotherapy is a powerful prognostic indicator of outcome and should be used to stratify the risk of patients in studies of relapsed follicular lymphoma,” the authors wrote.

The findings were validated in an independent cohort of patients with follicular lymphoma treated with R-CHOP from the University of Iowa and Mayo Clinical Molecular Epidemiology Resource, and are consistent with findings from other studies of patients treated with different rituximab-based regimens, the investigators reported.

In unadjusted analysis, early disease progression was associated with a hazard ratio (HR) of 7.17 (95% confidence interval [CI] 4.83-10.65); the effect remained after adjustment for the Follicular Lymphoma International Prognostic Index (FLIPI) score (HR 6.44, 95% CI, 4.33-9.58).

Factors associated with early progression included age, Eastern Cooperative Oncology Group performance score, nodal sites, and disease stage.

Early use of aggressive salvage therapies or autologous stem-cell transplantation could improve outcomes in patients with early disease progression, the authors wrote. However, only 8 patients among the 110 with early progression went on to transplant, not a large enough sample for meaningful analysis, they added.

“This newly defined high-risk group of patients represents a distinct population in whom further study is warranted in both directed prospective clinical trials of follicular lymphoma biology and treatment. Moreover, we propose that 2-year progression-free survival may be a practical and meaningful clinical end point for trials involving a chemoimmunotherapy backbone,” they concluded.

 

 

Pregnant woman

Photo by Nina Matthews

 

Researchers have again found evidence to suggest that tests used to identify chromosomal fetal disorders can detect occult malignancies in pregnant women.

In a study made public last month, non-invasive prenatal tests (NIPTs) revealed 2 cases of lymphoma and a case of ovarian cancer in expectant mothers.

In the new study, researchers showed that positive NIPT results were due to leukemia, lymphoma, or solid tumors in 10 expectant mothers.

The research was published in JAMA and presented at the 19th International Conference on Prenatal Diagnosis and Therapy in Washington, DC. Funding for the study was provided by Illumina, and company employees were involved in the research.

“We did this study because noninvasive prenatal testing using sequencing of cell-free DNA in the mother’s plasma is the fastest-growing area of prenatal testing and, indeed, of genomic medicine,” said study author Diana W. Bianchi, MD, of Tufts Medical Center in Boston, Massachusetts.

“As the volume of tests has expanded, we’ve become increasingly aware of the so-called “false-positive” cases. [A]pproximately 0.2% of the time, there is a discrepancy between the results of the prenatal test—in which an aneuploidy is reported—and the result from the diagnostic fetal procedure, the amniocentesis or the chorionic villus sampling.”

“So we’re interested in the situation where the fetal chromosomes are normal, but the prenatal test shows that there’s an aneuploidy detected. We’re interested in the possible explanations for that discrepancy.”

To gain some insight, Dr Bianchi and her colleagues evaluated 125,426 samples from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening using Illumina’s verifi Prenatal Test.

In all, 3757 samples (3%) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. These were reported to the ordering physician with recommendations for further evaluation.

“In a small minority of women, [subsequent tests analyzing only fetal DNA] showed that the fetal chromosomes were normal, and that disagreed with [results of the NIPT],” Dr Bianchi said. “We were examining whether cancer could explain the discrepancy between these two test results.”

The researchers found that 10 of the women with discordant test results were subsequently diagnosed with cancer. There were 3 cases of B-cell lymphoma and 1 case each of T-cell leukemia, Hodgkin lymphoma, unspecified adenocarcinoma, leiomyosarcoma, and neuroendocrine, colorectal, and anal carcinomas.

Dr Bianchi and her colleagues were able to obtain detailed clinical and sequencing data for 8 of these cases. In the other 2 cases (leiomyosarcoma and unspecified adenocarcinoma), the women were critically ill and were not approached about participating in the study.

The researchers found that maternal cancers most frequently occurred when the NIPT detected more than 1 aneuploidy. There were 7 known cancers among 39 cases of multiple aneuploidies by NIPT. In 1 case, blood was sampled after the patient completed treatment for colorectal cancer, and the abnormal pattern was no longer evident.

When the researchers examined additional genetic information for the women with cancer, they found unique patterns of nonspecific copy-number gains and losses across multiple chromosomes.

“[These women] had DNA imbalances all across the genome,” Dr Bianchi said. “The [NIPT] normally is only looking at DNA material from the chromosomes of clinical interest—chromosomes 13, 18, 21, X, and Y.”

“When we opened up their results to look at all of the chromosomes, there were multiple abnormalities in other places, such as chromosome 8, chromosome 6, etc. Each woman had a unique pattern that was abnormal in many places. This suggested that it was the tumor DNA that was being shed into her blood and was contributing to the abnormal pattern.”

Dr Bianchi stressed that the tumor DNA did not affect the babies. She said all were born healthy, although labor was induced early in one mother to facilitate her cancer treatment.

 

 

Pregnant woman

Photo by Nina Matthews

 

Researchers have again found evidence to suggest that tests used to identify chromosomal fetal disorders can detect occult malignancies in pregnant women.

In a study made public last month, non-invasive prenatal tests (NIPTs) revealed 2 cases of lymphoma and a case of ovarian cancer in expectant mothers.

In the new study, researchers showed that positive NIPT results were due to leukemia, lymphoma, or solid tumors in 10 expectant mothers.

The research was published in JAMA and presented at the 19th International Conference on Prenatal Diagnosis and Therapy in Washington, DC. Funding for the study was provided by Illumina, and company employees were involved in the research.

“We did this study because noninvasive prenatal testing using sequencing of cell-free DNA in the mother’s plasma is the fastest-growing area of prenatal testing and, indeed, of genomic medicine,” said study author Diana W. Bianchi, MD, of Tufts Medical Center in Boston, Massachusetts.

“As the volume of tests has expanded, we’ve become increasingly aware of the so-called “false-positive” cases. [A]pproximately 0.2% of the time, there is a discrepancy between the results of the prenatal test—in which an aneuploidy is reported—and the result from the diagnostic fetal procedure, the amniocentesis or the chorionic villus sampling.”

“So we’re interested in the situation where the fetal chromosomes are normal, but the prenatal test shows that there’s an aneuploidy detected. We’re interested in the possible explanations for that discrepancy.”

To gain some insight, Dr Bianchi and her colleagues evaluated 125,426 samples from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening using Illumina’s verifi Prenatal Test.

In all, 3757 samples (3%) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. These were reported to the ordering physician with recommendations for further evaluation.

“In a small minority of women, [subsequent tests analyzing only fetal DNA] showed that the fetal chromosomes were normal, and that disagreed with [results of the NIPT],” Dr Bianchi said. “We were examining whether cancer could explain the discrepancy between these two test results.”

The researchers found that 10 of the women with discordant test results were subsequently diagnosed with cancer. There were 3 cases of B-cell lymphoma and 1 case each of T-cell leukemia, Hodgkin lymphoma, unspecified adenocarcinoma, leiomyosarcoma, and neuroendocrine, colorectal, and anal carcinomas.

Dr Bianchi and her colleagues were able to obtain detailed clinical and sequencing data for 8 of these cases. In the other 2 cases (leiomyosarcoma and unspecified adenocarcinoma), the women were critically ill and were not approached about participating in the study.

The researchers found that maternal cancers most frequently occurred when the NIPT detected more than 1 aneuploidy. There were 7 known cancers among 39 cases of multiple aneuploidies by NIPT. In 1 case, blood was sampled after the patient completed treatment for colorectal cancer, and the abnormal pattern was no longer evident.

When the researchers examined additional genetic information for the women with cancer, they found unique patterns of nonspecific copy-number gains and losses across multiple chromosomes.

“[These women] had DNA imbalances all across the genome,” Dr Bianchi said. “The [NIPT] normally is only looking at DNA material from the chromosomes of clinical interest—chromosomes 13, 18, 21, X, and Y.”

“When we opened up their results to look at all of the chromosomes, there were multiple abnormalities in other places, such as chromosome 8, chromosome 6, etc. Each woman had a unique pattern that was abnormal in many places. This suggested that it was the tumor DNA that was being shed into her blood and was contributing to the abnormal pattern.”

Dr Bianchi stressed that the tumor DNA did not affect the babies. She said all were born healthy, although labor was induced early in one mother to facilitate her cancer treatment.

 

 

Pregnant woman

Photo by Nina Matthews

 

Researchers have again found evidence to suggest that tests used to identify chromosomal fetal disorders can detect occult malignancies in pregnant women.

In a study made public last month, non-invasive prenatal tests (NIPTs) revealed 2 cases of lymphoma and a case of ovarian cancer in expectant mothers.

In the new study, researchers showed that positive NIPT results were due to leukemia, lymphoma, or solid tumors in 10 expectant mothers.

The research was published in JAMA and presented at the 19th International Conference on Prenatal Diagnosis and Therapy in Washington, DC. Funding for the study was provided by Illumina, and company employees were involved in the research.

“We did this study because noninvasive prenatal testing using sequencing of cell-free DNA in the mother’s plasma is the fastest-growing area of prenatal testing and, indeed, of genomic medicine,” said study author Diana W. Bianchi, MD, of Tufts Medical Center in Boston, Massachusetts.

“As the volume of tests has expanded, we’ve become increasingly aware of the so-called “false-positive” cases. [A]pproximately 0.2% of the time, there is a discrepancy between the results of the prenatal test—in which an aneuploidy is reported—and the result from the diagnostic fetal procedure, the amniocentesis or the chorionic villus sampling.”

“So we’re interested in the situation where the fetal chromosomes are normal, but the prenatal test shows that there’s an aneuploidy detected. We’re interested in the possible explanations for that discrepancy.”

To gain some insight, Dr Bianchi and her colleagues evaluated 125,426 samples from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening using Illumina’s verifi Prenatal Test.

In all, 3757 samples (3%) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. These were reported to the ordering physician with recommendations for further evaluation.

“In a small minority of women, [subsequent tests analyzing only fetal DNA] showed that the fetal chromosomes were normal, and that disagreed with [results of the NIPT],” Dr Bianchi said. “We were examining whether cancer could explain the discrepancy between these two test results.”

The researchers found that 10 of the women with discordant test results were subsequently diagnosed with cancer. There were 3 cases of B-cell lymphoma and 1 case each of T-cell leukemia, Hodgkin lymphoma, unspecified adenocarcinoma, leiomyosarcoma, and neuroendocrine, colorectal, and anal carcinomas.

Dr Bianchi and her colleagues were able to obtain detailed clinical and sequencing data for 8 of these cases. In the other 2 cases (leiomyosarcoma and unspecified adenocarcinoma), the women were critically ill and were not approached about participating in the study.

The researchers found that maternal cancers most frequently occurred when the NIPT detected more than 1 aneuploidy. There were 7 known cancers among 39 cases of multiple aneuploidies by NIPT. In 1 case, blood was sampled after the patient completed treatment for colorectal cancer, and the abnormal pattern was no longer evident.

When the researchers examined additional genetic information for the women with cancer, they found unique patterns of nonspecific copy-number gains and losses across multiple chromosomes.

“[These women] had DNA imbalances all across the genome,” Dr Bianchi said. “The [NIPT] normally is only looking at DNA material from the chromosomes of clinical interest—chromosomes 13, 18, 21, X, and Y.”

“When we opened up their results to look at all of the chromosomes, there were multiple abnormalities in other places, such as chromosome 8, chromosome 6, etc. Each woman had a unique pattern that was abnormal in many places. This suggested that it was the tumor DNA that was being shed into her blood and was contributing to the abnormal pattern.”

Dr Bianchi stressed that the tumor DNA did not affect the babies. She said all were born healthy, although labor was induced early in one mother to facilitate her cancer treatment.

 

 

Patient receiving chemotherapy

Photo by Rhoda Baer

 

The goal for many cancer patients is to reach the 5-year mark without progression, but a new study suggests 2 years might be a more appropriate goal for patients with follicular lymphoma (FL).

Previous research indicated that about 20% of FL patients relapse within 2 years of treatment.

Now, researchers have found these patients have a significantly worse 5-year survival rate than patients who make it past the 2-year mark without progressing.

Carla Casulo, MD, of the University of Rochester in New York, and her colleagues recounted these findings in the Journal of Clinical Oncology.

The team analyzed data from 588 patients with stage 2-4 FL who received first-line therapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

These patients could be separated into 2 groups: those with disease progression within 2 years of diagnosis (19%, n=110) and those who did not progress within the 2-year period (71%, n=420).

Eight percent of patients (n=46) were lost to follow-up, and 2% (n=12) died of causes other than progression within the 2-year period.

At 2 years, the overall survival (OS) rate was 68% in the early progression group and 97% in the group that did not progress. At 5 years, OS rates were 50% and 90%, respectively.

In unadjusted Cox regression analysis, early progression was associated with lower OS (hazard ratio[HR]=7.17). The same was true after the researchers adjusted for FLIPI score (HR=6.44).

The team observed similar results in a validation cohort of 147 FL patients who received first-line R-CHOP. At 2 years, the OS rate was 64% in the early progression group and 98% in the group that did not progress. At 5 years, OS rates were 34% and 94%, respectively.

Again, in an unadjusted analysis, early progression was associated with lower OS (HR=20.0). And this trend was maintained after the researchers adjusted for FLIPI score (HR=19.8).

The researchers also found that, for patients in the early progression group, clinical factors that were predictive of inferior OS were age, ECOG performance score, nodal sites, and disease stage. For the group that did not progress within 2 years, clinical factors that were predictive of OS were age and extranodal sites.

In a Cox regression analysis that encompassed these factors and early progression, only early progression, age, and ECOG performance scores remained significantly predictive of OS.

“[W]e have confirmed that all relapsed patients are not equal and therefore should not be approached the same at diagnosis, nor at the time of relapse, in terms of therapies,” Dr Casulo said.

“It will be critical to predict who is most likely to relapse early. We believe that targeted sequencing or gene-expression profiling will be important to understanding how to improve the outcomes of this group.”

 

 

Patient receiving chemotherapy

Photo by Rhoda Baer

 

The goal for many cancer patients is to reach the 5-year mark without progression, but a new study suggests 2 years might be a more appropriate goal for patients with follicular lymphoma (FL).

Previous research indicated that about 20% of FL patients relapse within 2 years of treatment.

Now, researchers have found these patients have a significantly worse 5-year survival rate than patients who make it past the 2-year mark without progressing.

Carla Casulo, MD, of the University of Rochester in New York, and her colleagues recounted these findings in the Journal of Clinical Oncology.

The team analyzed data from 588 patients with stage 2-4 FL who received first-line therapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

These patients could be separated into 2 groups: those with disease progression within 2 years of diagnosis (19%, n=110) and those who did not progress within the 2-year period (71%, n=420).

Eight percent of patients (n=46) were lost to follow-up, and 2% (n=12) died of causes other than progression within the 2-year period.

At 2 years, the overall survival (OS) rate was 68% in the early progression group and 97% in the group that did not progress. At 5 years, OS rates were 50% and 90%, respectively.

In unadjusted Cox regression analysis, early progression was associated with lower OS (hazard ratio[HR]=7.17). The same was true after the researchers adjusted for FLIPI score (HR=6.44).

The team observed similar results in a validation cohort of 147 FL patients who received first-line R-CHOP. At 2 years, the OS rate was 64% in the early progression group and 98% in the group that did not progress. At 5 years, OS rates were 34% and 94%, respectively.

Again, in an unadjusted analysis, early progression was associated with lower OS (HR=20.0). And this trend was maintained after the researchers adjusted for FLIPI score (HR=19.8).

The researchers also found that, for patients in the early progression group, clinical factors that were predictive of inferior OS were age, ECOG performance score, nodal sites, and disease stage. For the group that did not progress within 2 years, clinical factors that were predictive of OS were age and extranodal sites.

In a Cox regression analysis that encompassed these factors and early progression, only early progression, age, and ECOG performance scores remained significantly predictive of OS.

“[W]e have confirmed that all relapsed patients are not equal and therefore should not be approached the same at diagnosis, nor at the time of relapse, in terms of therapies,” Dr Casulo said.

“It will be critical to predict who is most likely to relapse early. We believe that targeted sequencing or gene-expression profiling will be important to understanding how to improve the outcomes of this group.”

 

 

Patient receiving chemotherapy

Photo by Rhoda Baer

 

The goal for many cancer patients is to reach the 5-year mark without progression, but a new study suggests 2 years might be a more appropriate goal for patients with follicular lymphoma (FL).

Previous research indicated that about 20% of FL patients relapse within 2 years of treatment.

Now, researchers have found these patients have a significantly worse 5-year survival rate than patients who make it past the 2-year mark without progressing.

Carla Casulo, MD, of the University of Rochester in New York, and her colleagues recounted these findings in the Journal of Clinical Oncology.

The team analyzed data from 588 patients with stage 2-4 FL who received first-line therapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).

These patients could be separated into 2 groups: those with disease progression within 2 years of diagnosis (19%, n=110) and those who did not progress within the 2-year period (71%, n=420).

Eight percent of patients (n=46) were lost to follow-up, and 2% (n=12) died of causes other than progression within the 2-year period.

At 2 years, the overall survival (OS) rate was 68% in the early progression group and 97% in the group that did not progress. At 5 years, OS rates were 50% and 90%, respectively.

In unadjusted Cox regression analysis, early progression was associated with lower OS (hazard ratio[HR]=7.17). The same was true after the researchers adjusted for FLIPI score (HR=6.44).

The team observed similar results in a validation cohort of 147 FL patients who received first-line R-CHOP. At 2 years, the OS rate was 64% in the early progression group and 98% in the group that did not progress. At 5 years, OS rates were 34% and 94%, respectively.

Again, in an unadjusted analysis, early progression was associated with lower OS (HR=20.0). And this trend was maintained after the researchers adjusted for FLIPI score (HR=19.8).

The researchers also found that, for patients in the early progression group, clinical factors that were predictive of inferior OS were age, ECOG performance score, nodal sites, and disease stage. For the group that did not progress within 2 years, clinical factors that were predictive of OS were age and extranodal sites.

In a Cox regression analysis that encompassed these factors and early progression, only early progression, age, and ECOG performance scores remained significantly predictive of OS.

“[W]e have confirmed that all relapsed patients are not equal and therefore should not be approached the same at diagnosis, nor at the time of relapse, in terms of therapies,” Dr Casulo said.

“It will be critical to predict who is most likely to relapse early. We believe that targeted sequencing or gene-expression profiling will be important to understanding how to improve the outcomes of this group.”

 

 

Growing monoclonal antibodies

Photo by Linda Bartlett

 

LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.

Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.

In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.

Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.

Dr  Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.

Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.

Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.

The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.

Patient demographics

Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.

Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.

The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.

Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).

Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.

Safety

In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.

Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.

“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”

Efficacy outcomes

The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.

Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.

Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.

Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.

A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.

The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.

The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.

The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.

*Information in the abstract differs from that presented at the meeting.

 

 

Growing monoclonal antibodies

Photo by Linda Bartlett

 

LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.

Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.

In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.

Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.

Dr  Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.

Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.

Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.

The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.

Patient demographics

Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.

Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.

The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.

Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).

Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.

Safety

In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.

Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.

“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”

Efficacy outcomes

The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.

Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.

Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.

Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.

A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.

The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.

The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.

The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.

*Information in the abstract differs from that presented at the meeting.

 

 

Growing monoclonal antibodies

Photo by Linda Bartlett

 

LUGANO—The defucosylated monoclonal antibody (mAb) ARGX-110, which is active against CD70-bearing tumor cells and CD70-dependent stimulation of regulatory T cells, has shown activity in relapsed/refractory T-cell lymphoma (TCL), according to investigators.

Of the 8 TCL patients enrolled in a phase 1 trial of ARGX-110, 3 had a biological response to the mAb.

In this dose-escalation trial, the maximum tolerated dose of ARGX-110 was not reached.

Marie Maerevoet, MD, of the Institut Jules Bordet in Brussels, Belgium, presented results from the lymphoma cohort of this trial at the 13th International Congress on Malignant Lymphoma (abstract 040*). The study was sponsored by arGEN-X, the company developing ARGX-110.

Dr  Maerevoet pointed out that more than half the tumor cells in 71% of patients with cutaneous T-cell lymphoma (CTCL) and 22% with peripheral T-cell lymphoma (PTCL) are CD70-positive. CD70 signaling occurs via CD27, and CD27 shedding is a biomarker for an active pathway.

Since ARGX-110 has an affinity for CD70, inhibits CD27 signaling, and mediates the lysis of TCL in Sézary syndrome (SS), mycosis fungoides, and anaplastic large cell lymphoma (ALCL) cell lines, researchers decided to investigate the safety and clinical pharmacology of ARGX-110 monotherapy in metastatic, relapsed or refractory, solid tumors and hematologic malignancies.

Patients’ tumors had to express CD70 by immunohistochemistry, defined as more than 10% tumor cells of 2+ or 3+ intensity.

The primary endpoint was to determine the maximum tolerated dose. Secondary endpoints were pharmacology, immunogenicity, and efficacy signals.

Patient demographics

Between February 2013 and April 2015, investigators assigned 63 patients to receive ARGX-110 at doses ranging from 0.1 to 10 mg/kg intravenously once every 3 weeks until disease progression or withdrawal due to toxicity. Patients were pre-medicated with corticoid regimens.

Eighteen patients had lymphoid malignancies—8 with B-cell lymphomas, 8 with TCL, and 2 with Hodgkin lymphoma.

The TCL cohort consisted of 1 patient with SS, 1 with transformed SS, 1 with T-helper CTCL, 2 with angioimmunoblastic T-cell lymphoma (AITL), 2 with PTCL not otherwise specified (NOS), and 1 with ALCL.

Patients were a median age of 62 (range, 55–78), had a median of 4 prior treatment regimens (range, 2–6), and received a median of 2 cycles of ARGX-110 (range, 1–6).

Dr Maerevoet noted that most lymphoma patients received a dose of 5 mg/kg every 3 weeks.

Safety

In the entire lymphoma cohort of 18 patients, 4 patients (22%) experienced a grade 1 or 2 infusion-related reaction. Three patients (18%) developed grade 3 sepsis—1 with Waldenstrom’s macroglobulinemia, 1 with AITL, and 1 with PTCL-NOS.

Two patients (11%) had hematologic toxicity consisting of a grade 3 decrease in hemoglobin and absolute neutrophil count, which was considered not related to treatment with ARGX-110.

“The maximum tolerated dose was not reached,” Dr Maerevoet said. “We didn’t observe auto-immune adverse events or impact on serum IgG or IgM.”

Efficacy outcomes

The main reason for withdrawal was progressive disease, which occurred in 14 lymphoma patients.

Two patients—1 with Waldenstrom’s macroglobulinemia and 1 with AITL—withdrew due to adverse events of sepsis (catheter infection, pneumonia), 1 patient with SS withdrew for social reasons, and 1 patient with follicular T-cell lymphoma (currently classified as PTCL-NOS) remains on study.

Dr Maerevoet described the 3 TCL patients who had a biologic response to ARGX-110. One patient with SS had a hematologic complete remission after 6 cycles at the 0.1 mg/kg dose.

Another patient with transformed SS experienced a depletion of circulating clones after 2 cycles of the 10 mg/kg dose. However, the patient ultimately died of progressive disease.

A third patient had resolution of autoimmune hemolytic anemia. This 61-year-old male with AITL achieved a partial response with normalization of LDH levels and an increase in hemoglobin to 7.9 g/dL without transfusion support after 2 doses of ARGX-110 at 5 mg/kg.

The patient became Coombs-negative and had a 16% reduction in tumor size by CT scan. However, the patient subsequently died of pneumonia.

The investigators also observed clinical activity in the peripheral blood, lymph nodes, and skin of 2 additional patients.

The biological activity of ARGX-110 as demonstrated by these TCL patients, in addition to the safety and tolerability of this mAb, led the team to conclude that further clinical investigation of ARGX-110 in TCL is warranted.

*Information in the abstract differs from that presented at the meeting.

In patients with newly diagnosed lymphoma and suspected lymphoma, a second pathological review found inaccuracies in the original diagnosis among 17% of more than 42,000 cases, based on data presented at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

In more than 25% of all discrepancies, tumors were reclassified at the second pathology review as the result of findings from additional immunostaining and molecular studies – polymerase chain reaction and fluorescence in situ hybridization.

In 15% of cases, diagnostic changes were expected to result in a change in patient management.

“Our study highlights the importance of specialized centralized review of lymphoma diagnosis, not only in the setting of clinical trials but also in routine clinical practice, for optimal patient management,” reported Dr. Camille Laurent of the Institut Universitaire du Cancer Oncopole, Toulouse, France.

In 2010, the French National Cancer Agency (INCa) established the Lymphopath Network, comprising 33 reference centers, to provide a review by expert hematopathologists of every newly diagnosed lymphoma or suspected lymphoma prior to treatment. These new diagnoses were entered in a central national database. Between 2010 and 2015, 42,146 samples were reviewed: 35,753 were newly diagnosed as lymphomas, while the remaining 6,393 cases included 4,610 reactive lymphoid conditions and 1,783 nonlymphoid malignancies, including especially myeloma and leukemic disorders.

Discordant diagnoses among extra-cutaneous lymphomas were carefully examined by a hematologist and recorded as major or minor depending on the expected therapeutic impact. Dr. Laurent said.

The discordance rate between the referral diagnosis and the final diagnosis was 17.2%. Small B-cell lymphomas and peripheral T-cell lymphoma subtyping were the most common discrepancies; 6.4% of discordances were due to an unspecified lymphoma diagnosis, Dr. Laurent stated.

Less than 2% of discrepancies were due to misclassifications of benign versus malignant lymphoid conditions and of Hodgkin lymphoma versus non-Hodgkin lymphoma. There were minor discrepancies (2.2%) in follicular lymphoma misgrading and diffuse large B-cell lymphoma subtypes.

In patients with newly diagnosed lymphoma and suspected lymphoma, a second pathological review found inaccuracies in the original diagnosis among 17% of more than 42,000 cases, based on data presented at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

In more than 25% of all discrepancies, tumors were reclassified at the second pathology review as the result of findings from additional immunostaining and molecular studies – polymerase chain reaction and fluorescence in situ hybridization.

In 15% of cases, diagnostic changes were expected to result in a change in patient management.

“Our study highlights the importance of specialized centralized review of lymphoma diagnosis, not only in the setting of clinical trials but also in routine clinical practice, for optimal patient management,” reported Dr. Camille Laurent of the Institut Universitaire du Cancer Oncopole, Toulouse, France.

In 2010, the French National Cancer Agency (INCa) established the Lymphopath Network, comprising 33 reference centers, to provide a review by expert hematopathologists of every newly diagnosed lymphoma or suspected lymphoma prior to treatment. These new diagnoses were entered in a central national database. Between 2010 and 2015, 42,146 samples were reviewed: 35,753 were newly diagnosed as lymphomas, while the remaining 6,393 cases included 4,610 reactive lymphoid conditions and 1,783 nonlymphoid malignancies, including especially myeloma and leukemic disorders.

Discordant diagnoses among extra-cutaneous lymphomas were carefully examined by a hematologist and recorded as major or minor depending on the expected therapeutic impact. Dr. Laurent said.

The discordance rate between the referral diagnosis and the final diagnosis was 17.2%. Small B-cell lymphomas and peripheral T-cell lymphoma subtyping were the most common discrepancies; 6.4% of discordances were due to an unspecified lymphoma diagnosis, Dr. Laurent stated.

Less than 2% of discrepancies were due to misclassifications of benign versus malignant lymphoid conditions and of Hodgkin lymphoma versus non-Hodgkin lymphoma. There were minor discrepancies (2.2%) in follicular lymphoma misgrading and diffuse large B-cell lymphoma subtypes.

In patients with newly diagnosed lymphoma and suspected lymphoma, a second pathological review found inaccuracies in the original diagnosis among 17% of more than 42,000 cases, based on data presented at the International Congress on Malignant Lymphoma in Lugano, Switzerland.

In more than 25% of all discrepancies, tumors were reclassified at the second pathology review as the result of findings from additional immunostaining and molecular studies – polymerase chain reaction and fluorescence in situ hybridization.

In 15% of cases, diagnostic changes were expected to result in a change in patient management.

“Our study highlights the importance of specialized centralized review of lymphoma diagnosis, not only in the setting of clinical trials but also in routine clinical practice, for optimal patient management,” reported Dr. Camille Laurent of the Institut Universitaire du Cancer Oncopole, Toulouse, France.

In 2010, the French National Cancer Agency (INCa) established the Lymphopath Network, comprising 33 reference centers, to provide a review by expert hematopathologists of every newly diagnosed lymphoma or suspected lymphoma prior to treatment. These new diagnoses were entered in a central national database. Between 2010 and 2015, 42,146 samples were reviewed: 35,753 were newly diagnosed as lymphomas, while the remaining 6,393 cases included 4,610 reactive lymphoid conditions and 1,783 nonlymphoid malignancies, including especially myeloma and leukemic disorders.

Discordant diagnoses among extra-cutaneous lymphomas were carefully examined by a hematologist and recorded as major or minor depending on the expected therapeutic impact. Dr. Laurent said.

The discordance rate between the referral diagnosis and the final diagnosis was 17.2%. Small B-cell lymphomas and peripheral T-cell lymphoma subtyping were the most common discrepancies; 6.4% of discordances were due to an unspecified lymphoma diagnosis, Dr. Laurent stated.

Less than 2% of discrepancies were due to misclassifications of benign versus malignant lymphoid conditions and of Hodgkin lymphoma versus non-Hodgkin lymphoma. There were minor discrepancies (2.2%) in follicular lymphoma misgrading and diffuse large B-cell lymphoma subtypes.

VIENNA – The investigational dual HDAC and Pi3K inhibitor CUDC-907 was reasonably tolerated and clinically active in a phase I study of relapsed or refractory lymphomas and multiple myeloma.

Among 44 patients evaluable for response, 7 had objective responses (16%).

Two complete and four partial responses occurred in 10 evaluable patients with diffuse large B-cell lymphoma (DLBCL).

One partial response was reported in 12 evaluable patients with Hodgkin lymphoma.

Stable disease was the best response in 4 of 6 evaluable patients with multiple myeloma and 11 of 16 patients with other lymphomas, Dr. Yasuhiro Oki reported at the annual congress of the European Hematology Association.

The first-in-human trial enrolled 57 patients with lymphoma (DLBCL, Hodgkin, Burkitt, follicular, gray zone, lymphoplasmacytic, mantle cell, marginal zone, and small lymphocytic) or multiple myeloma that was refractory to or relapsed after at least two prior regimens.

The median number of prior regimens was 5 (range 2-10), including prior histone deacetylase (HDAC) inhibitors in 11% and prior phosphatidylinositol 3-kinase (Pi3K) inhibitors in 9%.

The 3+3 design tested three different once-daily dosing schedules for the oral small molecule: 30 mg and 60 mg, 5 days on and 2 days off (5/2) 60 mg, and intermittent twice- or thrice-weekly at 60 mg, 90 mg, 120 mg, and 150 mg. The safety and efficacy data are from the completed dose escalation and ongoing expansion stages of the phase I trial with CUDC-907 administered as monotherapy.

Median treatment duration in the DLBCL group was 3 months, with treatment ongoing in some patients beyond 2 years. Long-term responders have included three patients with transformed follicular lymphoma (t-FL)/DLBCL, one with so-called triple-hit status involving translocations/rearrangements of MYC, BCL-2, and BCL-6 genes, according to Dr. Oki of University of Texas MD Anderson Cancer Center in Houston.

The patient with Hodgkin lymphoma who responded had failed four prior therapies, but experienced a 42% reduction in tumor size on imaging by cycle two and a partial response to 60 mg 5/2 CUDC-907 by cycle six.

At least one adverse event (AE) occurred in 50 of the 57 patients, but AEs have been reversible with standard interventions, dose holds, or dose reductions, he added.

The most common grade 3/4 AEs reported in two or more patients were diarrhea, hyperglycemia, fatigue, thrombocytopenia, and decreased neutrophils.

Four dose-limiting toxicities occurred in three patients: grade 3 diarrhea in the 60-mg once-daily and 150-mg thrice-weekly dose groups and grade 4 hyperglycemia in the 60-mg once-daily and 150-mg twice-weekly dose groups.

“The 5/2 60-mg and thrice-weekly 120-mg dosing was found to be reasonably tolerated while still achieving objective responses,” Dr. Oki noted in the poster.

The ongoing expansion phase is evaluating CUDC-907 at the recommended phase II doses of 60 mg 5/2 and 120 mg thrice-weekly in patients with relapsed refractory DLBCL, Hodgkin lymphoma, and multiple myeloma.

The trial is currently enrolling patients with DLBCL for treatment with CUDC-907 monotherapy and in combination with standard-dose rituximab.

Phase II testing of CUDC-907 in combination with rituximab in relapsed/refractory DLBCL is projected to start at the earliest in fourth-quarter 2015, according to the authors.

CUDC-907 (60 mg 5/2 and 120 mg three times weekly) is also being evaluated in advanced or relapsed solid tumors in an ongoing phase I trial.

[email protected]

On Twitter@pwendl

VIENNA – The investigational dual HDAC and Pi3K inhibitor CUDC-907 was reasonably tolerated and clinically active in a phase I study of relapsed or refractory lymphomas and multiple myeloma.

Among 44 patients evaluable for response, 7 had objective responses (16%).

Two complete and four partial responses occurred in 10 evaluable patients with diffuse large B-cell lymphoma (DLBCL).

One partial response was reported in 12 evaluable patients with Hodgkin lymphoma.

Stable disease was the best response in 4 of 6 evaluable patients with multiple myeloma and 11 of 16 patients with other lymphomas, Dr. Yasuhiro Oki reported at the annual congress of the European Hematology Association.

The first-in-human trial enrolled 57 patients with lymphoma (DLBCL, Hodgkin, Burkitt, follicular, gray zone, lymphoplasmacytic, mantle cell, marginal zone, and small lymphocytic) or multiple myeloma that was refractory to or relapsed after at least two prior regimens.

The median number of prior regimens was 5 (range 2-10), including prior histone deacetylase (HDAC) inhibitors in 11% and prior phosphatidylinositol 3-kinase (Pi3K) inhibitors in 9%.

The 3+3 design tested three different once-daily dosing schedules for the oral small molecule: 30 mg and 60 mg, 5 days on and 2 days off (5/2) 60 mg, and intermittent twice- or thrice-weekly at 60 mg, 90 mg, 120 mg, and 150 mg. The safety and efficacy data are from the completed dose escalation and ongoing expansion stages of the phase I trial with CUDC-907 administered as monotherapy.

Median treatment duration in the DLBCL group was 3 months, with treatment ongoing in some patients beyond 2 years. Long-term responders have included three patients with transformed follicular lymphoma (t-FL)/DLBCL, one with so-called triple-hit status involving translocations/rearrangements of MYC, BCL-2, and BCL-6 genes, according to Dr. Oki of University of Texas MD Anderson Cancer Center in Houston.

The patient with Hodgkin lymphoma who responded had failed four prior therapies, but experienced a 42% reduction in tumor size on imaging by cycle two and a partial response to 60 mg 5/2 CUDC-907 by cycle six.

At least one adverse event (AE) occurred in 50 of the 57 patients, but AEs have been reversible with standard interventions, dose holds, or dose reductions, he added.

The most common grade 3/4 AEs reported in two or more patients were diarrhea, hyperglycemia, fatigue, thrombocytopenia, and decreased neutrophils.

Four dose-limiting toxicities occurred in three patients: grade 3 diarrhea in the 60-mg once-daily and 150-mg thrice-weekly dose groups and grade 4 hyperglycemia in the 60-mg once-daily and 150-mg twice-weekly dose groups.

“The 5/2 60-mg and thrice-weekly 120-mg dosing was found to be reasonably tolerated while still achieving objective responses,” Dr. Oki noted in the poster.

The ongoing expansion phase is evaluating CUDC-907 at the recommended phase II doses of 60 mg 5/2 and 120 mg thrice-weekly in patients with relapsed refractory DLBCL, Hodgkin lymphoma, and multiple myeloma.

The trial is currently enrolling patients with DLBCL for treatment with CUDC-907 monotherapy and in combination with standard-dose rituximab.

Phase II testing of CUDC-907 in combination with rituximab in relapsed/refractory DLBCL is projected to start at the earliest in fourth-quarter 2015, according to the authors.

CUDC-907 (60 mg 5/2 and 120 mg three times weekly) is also being evaluated in advanced or relapsed solid tumors in an ongoing phase I trial.

[email protected]

On Twitter@pwendl

VIENNA – The investigational dual HDAC and Pi3K inhibitor CUDC-907 was reasonably tolerated and clinically active in a phase I study of relapsed or refractory lymphomas and multiple myeloma.

Among 44 patients evaluable for response, 7 had objective responses (16%).

Two complete and four partial responses occurred in 10 evaluable patients with diffuse large B-cell lymphoma (DLBCL).

One partial response was reported in 12 evaluable patients with Hodgkin lymphoma.

Stable disease was the best response in 4 of 6 evaluable patients with multiple myeloma and 11 of 16 patients with other lymphomas, Dr. Yasuhiro Oki reported at the annual congress of the European Hematology Association.

The first-in-human trial enrolled 57 patients with lymphoma (DLBCL, Hodgkin, Burkitt, follicular, gray zone, lymphoplasmacytic, mantle cell, marginal zone, and small lymphocytic) or multiple myeloma that was refractory to or relapsed after at least two prior regimens.

The median number of prior regimens was 5 (range 2-10), including prior histone deacetylase (HDAC) inhibitors in 11% and prior phosphatidylinositol 3-kinase (Pi3K) inhibitors in 9%.

The 3+3 design tested three different once-daily dosing schedules for the oral small molecule: 30 mg and 60 mg, 5 days on and 2 days off (5/2) 60 mg, and intermittent twice- or thrice-weekly at 60 mg, 90 mg, 120 mg, and 150 mg. The safety and efficacy data are from the completed dose escalation and ongoing expansion stages of the phase I trial with CUDC-907 administered as monotherapy.

Median treatment duration in the DLBCL group was 3 months, with treatment ongoing in some patients beyond 2 years. Long-term responders have included three patients with transformed follicular lymphoma (t-FL)/DLBCL, one with so-called triple-hit status involving translocations/rearrangements of MYC, BCL-2, and BCL-6 genes, according to Dr. Oki of University of Texas MD Anderson Cancer Center in Houston.

The patient with Hodgkin lymphoma who responded had failed four prior therapies, but experienced a 42% reduction in tumor size on imaging by cycle two and a partial response to 60 mg 5/2 CUDC-907 by cycle six.

At least one adverse event (AE) occurred in 50 of the 57 patients, but AEs have been reversible with standard interventions, dose holds, or dose reductions, he added.

The most common grade 3/4 AEs reported in two or more patients were diarrhea, hyperglycemia, fatigue, thrombocytopenia, and decreased neutrophils.

Four dose-limiting toxicities occurred in three patients: grade 3 diarrhea in the 60-mg once-daily and 150-mg thrice-weekly dose groups and grade 4 hyperglycemia in the 60-mg once-daily and 150-mg twice-weekly dose groups.

“The 5/2 60-mg and thrice-weekly 120-mg dosing was found to be reasonably tolerated while still achieving objective responses,” Dr. Oki noted in the poster.

The ongoing expansion phase is evaluating CUDC-907 at the recommended phase II doses of 60 mg 5/2 and 120 mg thrice-weekly in patients with relapsed refractory DLBCL, Hodgkin lymphoma, and multiple myeloma.

The trial is currently enrolling patients with DLBCL for treatment with CUDC-907 monotherapy and in combination with standard-dose rituximab.

Phase II testing of CUDC-907 in combination with rituximab in relapsed/refractory DLBCL is projected to start at the earliest in fourth-quarter 2015, according to the authors.

CUDC-907 (60 mg 5/2 and 120 mg three times weekly) is also being evaluated in advanced or relapsed solid tumors in an ongoing phase I trial.

[email protected]

On Twitter@pwendl

 

 

Micrograph showing DLBCL

 

LUGANO—The phase 1, first-in-human study of the novel SYK inhibitor TAK-659 is showing “good early evidence” of antitumor activity in patients with lymphoma, according to investigators.

The agent also appears to be fairly well tolerated, with 10 categories of adverse events occurring in 2 or more patients.

Adam M. Petrich, MD, of Northwestern University in Evanston, Illinois, presented results from this ongoing study at the 13th International Congress on Malignant Lymphoma (13-ICML) as abstract 039.*

The study is supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Dr Petrich said the B-cell receptor signaling pathway is “very fertile ground with respect to development for novel targeting, particularly of B-cell malignancies, and SYK—the spleen tyrosine kinase—is an integral component of this.”

Investigators believe SYK has implications beyond B-cell lymphoma, including EBV-related malignancies, solid tumors, and myeloid leukemias.

Preclinical findings

In vitro experiments with TAK-659 showed “profound inhibition” of both SYK and FLT3, as indicated by the low IC₅₀ levels, Dr Petrich said.

He also pointed out that the EC₅₀ levels compare favorably to ibrutinib and idelalisib, with generally lower numbers in a broad panel of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia.

In animal models, TAK-659 exhibited a dose-dependent tumor-inhibitory property.

“And if we look at both germinal center B and non-germinal center B subtypes of large-cell lymphoma, we see activity across both types,” Dr Petrich said.

Phase 1 study

Investigators are currently conducting the phase 1 study, which is a standard 3+3 dose-escalation schema. The data cutoff for the ICML presentation was April 13, although the dose-escalation phase was still underway, and the maximum tolerated dose was not yet reached.

Based on preclinical data, the team projected the efficacious dose for humans to be approximately 600 to 1200 mg per day. Patients were started at 60 mg, and, at the next planned step of 120 mg, 2 patients developed asymptomatic lipase elevations.

“For that reason, we revised the protocol, allowed for those to not be considered dose-limiting toxicities, and explored intermediate doses,” Dr Petrich explained.

So the protocol now includes intermediate doses of 80 and 100 mg. Dr Petrich’s presentation focused on the 4 doses—60, 80, 100, and 120 mg taken orally once daily.

He said the observed human clearance of TAK-659 was approximately 3- to 4-fold lower than predicted based on the mouse pharmacokinetic (PK) data, which led to steady-state area under the curve values 3- to 4-fold higher in humans than predicted.

Patient demographics

The investigators enrolled 21 patients, 12 with solid tumors, 6 with DLBCL, and 3 with FL. The median age was 60 years, 66% were male, and 62% had received 4 or more prior therapies.

The median number of TAK-659 treatment cycles was 2 (range, 1–10), and 5 patients are still on active treatment. Dr Petrich pointed out that 4 of the 5 longest-treated patients have DLBCL, and “the record holder with DLBCL is about to celebrate 1 year on therapy.”

Safety

“The safety profile in humans showed that [TAK-659] was actually quite tolerable,” Dr Petrich said.

There were 10 categories of treatment-related adverse events (AEs) that occurred in 2 or more patients. They were, in descending order, fatigue, anemia, diarrhea, elevated AST, hypophosphatemia, nausea, rash, elevated lipase, elevated ALT, and anorexia.

The majority of AEs were grade 1 or 2. However, there were grade 3/4 cases of anemia, diarrhea, elevated AST, and hypophosphatemia. And elevated lipase—the asymptomatic, dose-limiting toxicity for which the protocol was modified—consisted entirely of grade 3 or 4 events.

Episodes of neutropenia and thrombocytopenia occurred in 1 patient each, and both were grade 1.

“So [TAK-659] seems quite well tolerated in that regard as well,” Dr Petrich observed.

The plasma profile on days 1 and 15 of cycle 1 indicate that PK steady-state conditions are generally achieved by day 8, with moderate accumulation after repeated, once-daily dosing for 15 days.

Antitumor activity

Of the 12 evaluable patients, 5 had tumor shrinkage at the 60, 80, or 100 mg dose levels. Three of the 6 DLBCL patients experienced tumor shrinkage, and there were “2 dramatic responses in patients with follicular lymphoma, including 1 CR [complete response],” Dr Petrich said.

One of these FL patients had an aggressive phenotype and never had a previous response last longer than 20 months.

“[H]e actually achieved a CR within 2 cycles—a dramatic response for his disease—and he remains on treatment, and he’s up to cycle 5 now,” Dr Petrich said.

The team concluded that the PK data support daily dosing, despite lower clearance than originally predicted.

“[There is] good early evidence of antitumor activity and no significant safety signals,” Dr Petrich said. “And the [hematologic] toxicity profile, in particular, seems to suggest this is a well-tolerated drug.”

The investigators are conducting expansion cohorts and are considering future combination studies. They recently activated a study in acute myeloid leukemia because TAK-659 has FLT3 inhibitory properties.  

*Information in the abstract differs from that presented at the meeting.

 

 

Micrograph showing DLBCL

 

LUGANO—The phase 1, first-in-human study of the novel SYK inhibitor TAK-659 is showing “good early evidence” of antitumor activity in patients with lymphoma, according to investigators.

The agent also appears to be fairly well tolerated, with 10 categories of adverse events occurring in 2 or more patients.

Adam M. Petrich, MD, of Northwestern University in Evanston, Illinois, presented results from this ongoing study at the 13th International Congress on Malignant Lymphoma (13-ICML) as abstract 039.*

The study is supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Dr Petrich said the B-cell receptor signaling pathway is “very fertile ground with respect to development for novel targeting, particularly of B-cell malignancies, and SYK—the spleen tyrosine kinase—is an integral component of this.”

Investigators believe SYK has implications beyond B-cell lymphoma, including EBV-related malignancies, solid tumors, and myeloid leukemias.

Preclinical findings

In vitro experiments with TAK-659 showed “profound inhibition” of both SYK and FLT3, as indicated by the low IC₅₀ levels, Dr Petrich said.

He also pointed out that the EC₅₀ levels compare favorably to ibrutinib and idelalisib, with generally lower numbers in a broad panel of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia.

In animal models, TAK-659 exhibited a dose-dependent tumor-inhibitory property.

“And if we look at both germinal center B and non-germinal center B subtypes of large-cell lymphoma, we see activity across both types,” Dr Petrich said.

Phase 1 study

Investigators are currently conducting the phase 1 study, which is a standard 3+3 dose-escalation schema. The data cutoff for the ICML presentation was April 13, although the dose-escalation phase was still underway, and the maximum tolerated dose was not yet reached.

Based on preclinical data, the team projected the efficacious dose for humans to be approximately 600 to 1200 mg per day. Patients were started at 60 mg, and, at the next planned step of 120 mg, 2 patients developed asymptomatic lipase elevations.

“For that reason, we revised the protocol, allowed for those to not be considered dose-limiting toxicities, and explored intermediate doses,” Dr Petrich explained.

So the protocol now includes intermediate doses of 80 and 100 mg. Dr Petrich’s presentation focused on the 4 doses—60, 80, 100, and 120 mg taken orally once daily.

He said the observed human clearance of TAK-659 was approximately 3- to 4-fold lower than predicted based on the mouse pharmacokinetic (PK) data, which led to steady-state area under the curve values 3- to 4-fold higher in humans than predicted.

Patient demographics

The investigators enrolled 21 patients, 12 with solid tumors, 6 with DLBCL, and 3 with FL. The median age was 60 years, 66% were male, and 62% had received 4 or more prior therapies.

The median number of TAK-659 treatment cycles was 2 (range, 1–10), and 5 patients are still on active treatment. Dr Petrich pointed out that 4 of the 5 longest-treated patients have DLBCL, and “the record holder with DLBCL is about to celebrate 1 year on therapy.”

Safety

“The safety profile in humans showed that [TAK-659] was actually quite tolerable,” Dr Petrich said.

There were 10 categories of treatment-related adverse events (AEs) that occurred in 2 or more patients. They were, in descending order, fatigue, anemia, diarrhea, elevated AST, hypophosphatemia, nausea, rash, elevated lipase, elevated ALT, and anorexia.

The majority of AEs were grade 1 or 2. However, there were grade 3/4 cases of anemia, diarrhea, elevated AST, and hypophosphatemia. And elevated lipase—the asymptomatic, dose-limiting toxicity for which the protocol was modified—consisted entirely of grade 3 or 4 events.

Episodes of neutropenia and thrombocytopenia occurred in 1 patient each, and both were grade 1.

“So [TAK-659] seems quite well tolerated in that regard as well,” Dr Petrich observed.

The plasma profile on days 1 and 15 of cycle 1 indicate that PK steady-state conditions are generally achieved by day 8, with moderate accumulation after repeated, once-daily dosing for 15 days.

Antitumor activity

Of the 12 evaluable patients, 5 had tumor shrinkage at the 60, 80, or 100 mg dose levels. Three of the 6 DLBCL patients experienced tumor shrinkage, and there were “2 dramatic responses in patients with follicular lymphoma, including 1 CR [complete response],” Dr Petrich said.

One of these FL patients had an aggressive phenotype and never had a previous response last longer than 20 months.

“[H]e actually achieved a CR within 2 cycles—a dramatic response for his disease—and he remains on treatment, and he’s up to cycle 5 now,” Dr Petrich said.

The team concluded that the PK data support daily dosing, despite lower clearance than originally predicted.

“[There is] good early evidence of antitumor activity and no significant safety signals,” Dr Petrich said. “And the [hematologic] toxicity profile, in particular, seems to suggest this is a well-tolerated drug.”

The investigators are conducting expansion cohorts and are considering future combination studies. They recently activated a study in acute myeloid leukemia because TAK-659 has FLT3 inhibitory properties.  

*Information in the abstract differs from that presented at the meeting.

 

 

Micrograph showing DLBCL

 

LUGANO—The phase 1, first-in-human study of the novel SYK inhibitor TAK-659 is showing “good early evidence” of antitumor activity in patients with lymphoma, according to investigators.

The agent also appears to be fairly well tolerated, with 10 categories of adverse events occurring in 2 or more patients.

Adam M. Petrich, MD, of Northwestern University in Evanston, Illinois, presented results from this ongoing study at the 13th International Congress on Malignant Lymphoma (13-ICML) as abstract 039.*

The study is supported by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.

Dr Petrich said the B-cell receptor signaling pathway is “very fertile ground with respect to development for novel targeting, particularly of B-cell malignancies, and SYK—the spleen tyrosine kinase—is an integral component of this.”

Investigators believe SYK has implications beyond B-cell lymphoma, including EBV-related malignancies, solid tumors, and myeloid leukemias.

Preclinical findings

In vitro experiments with TAK-659 showed “profound inhibition” of both SYK and FLT3, as indicated by the low IC₅₀ levels, Dr Petrich said.

He also pointed out that the EC₅₀ levels compare favorably to ibrutinib and idelalisib, with generally lower numbers in a broad panel of diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia.

In animal models, TAK-659 exhibited a dose-dependent tumor-inhibitory property.

“And if we look at both germinal center B and non-germinal center B subtypes of large-cell lymphoma, we see activity across both types,” Dr Petrich said.

Phase 1 study

Investigators are currently conducting the phase 1 study, which is a standard 3+3 dose-escalation schema. The data cutoff for the ICML presentation was April 13, although the dose-escalation phase was still underway, and the maximum tolerated dose was not yet reached.

Based on preclinical data, the team projected the efficacious dose for humans to be approximately 600 to 1200 mg per day. Patients were started at 60 mg, and, at the next planned step of 120 mg, 2 patients developed asymptomatic lipase elevations.

“For that reason, we revised the protocol, allowed for those to not be considered dose-limiting toxicities, and explored intermediate doses,” Dr Petrich explained.

So the protocol now includes intermediate doses of 80 and 100 mg. Dr Petrich’s presentation focused on the 4 doses—60, 80, 100, and 120 mg taken orally once daily.

He said the observed human clearance of TAK-659 was approximately 3- to 4-fold lower than predicted based on the mouse pharmacokinetic (PK) data, which led to steady-state area under the curve values 3- to 4-fold higher in humans than predicted.

Patient demographics

The investigators enrolled 21 patients, 12 with solid tumors, 6 with DLBCL, and 3 with FL. The median age was 60 years, 66% were male, and 62% had received 4 or more prior therapies.

The median number of TAK-659 treatment cycles was 2 (range, 1–10), and 5 patients are still on active treatment. Dr Petrich pointed out that 4 of the 5 longest-treated patients have DLBCL, and “the record holder with DLBCL is about to celebrate 1 year on therapy.”

Safety

“The safety profile in humans showed that [TAK-659] was actually quite tolerable,” Dr Petrich said.

There were 10 categories of treatment-related adverse events (AEs) that occurred in 2 or more patients. They were, in descending order, fatigue, anemia, diarrhea, elevated AST, hypophosphatemia, nausea, rash, elevated lipase, elevated ALT, and anorexia.

The majority of AEs were grade 1 or 2. However, there were grade 3/4 cases of anemia, diarrhea, elevated AST, and hypophosphatemia. And elevated lipase—the asymptomatic, dose-limiting toxicity for which the protocol was modified—consisted entirely of grade 3 or 4 events.

Episodes of neutropenia and thrombocytopenia occurred in 1 patient each, and both were grade 1.

“So [TAK-659] seems quite well tolerated in that regard as well,” Dr Petrich observed.

The plasma profile on days 1 and 15 of cycle 1 indicate that PK steady-state conditions are generally achieved by day 8, with moderate accumulation after repeated, once-daily dosing for 15 days.

Antitumor activity

Of the 12 evaluable patients, 5 had tumor shrinkage at the 60, 80, or 100 mg dose levels. Three of the 6 DLBCL patients experienced tumor shrinkage, and there were “2 dramatic responses in patients with follicular lymphoma, including 1 CR [complete response],” Dr Petrich said.

One of these FL patients had an aggressive phenotype and never had a previous response last longer than 20 months.

“[H]e actually achieved a CR within 2 cycles—a dramatic response for his disease—and he remains on treatment, and he’s up to cycle 5 now,” Dr Petrich said.

The team concluded that the PK data support daily dosing, despite lower clearance than originally predicted.

“[There is] good early evidence of antitumor activity and no significant safety signals,” Dr Petrich said. “And the [hematologic] toxicity profile, in particular, seems to suggest this is a well-tolerated drug.”

The investigators are conducting expansion cohorts and are considering future combination studies. They recently activated a study in acute myeloid leukemia because TAK-659 has FLT3 inhibitory properties.  

*Information in the abstract differs from that presented at the meeting.

Patients with follicular lymphoma who relapse within 2 years of receiving R-CHOP chemoimmunotherapy are at high risk of death, unlike those who do not relapse early, according to a report published online in Journal of Clinical Oncology.

Survival in follicular lymphoma, the second most common non-Hodgkin lymphoma in the United States, has dramatically improved over time, and the median survival after first-line chemoimmunotherapy now exceeds 18 years. But researchers have noted a remarkably consistent 20% rate of early relapse across numerous forms of treatment and varied study populations. Until now, the clinical significance of early relapse and its impact on overall survival has not been explored, said Dr. Carla Casulo of the University of Rochester, New York, and her associates.

They examined this issue using data from a national cohort of patients with newly diagnosed follicular lymphoma, focusing on 588 patients with stage II, III, or IV disease who were treated using first-line rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). A total of 19% of these patients relapsed within 24 months of diagnosis. Median follow-up was 7 years. With early disease progression, overall survival was only 68% at 2 years and only 50% at 5 years, compared with 97% and 90%, respectively, among patients who didn’t have early disease progression. Early progression was associated with markedly reduced survival, with a hazard ratio of 7.17.

To verify their findings in a separate cohort, Dr. Casulo and her associates assessed survival in 147 similar patients participating in a different study who were followed for a mean of 5.5 years. A total of 26% of this cohort had early relapse after receiving a variety of first-line chemoimmunotherapy regimens. With early disease progression, overall survival was only 64% at 2 years and only 34% at 5 years, compared with 98% and 94%, respectively, among patients who didn’t have early progression. Again, early progression was associated with markedly reduced survival, with an HR of 20.0 (J. Clin. Oncol. 2015 June 29 [doi: 10.1200/JCO.2014.59.7534]).

These two studies confirm that patients with follicular lymphoma who relapse within 2 years constitute a distinct subgroup at very high risk of death. “Given their poor prognosis, consideration of aggressive second-line treatments, including possibly autologous stem-cell transplantation, seem reasonable,” the investigators said.

Patients with follicular lymphoma who relapse within 2 years of receiving R-CHOP chemoimmunotherapy are at high risk of death, unlike those who do not relapse early, according to a report published online in Journal of Clinical Oncology.

Survival in follicular lymphoma, the second most common non-Hodgkin lymphoma in the United States, has dramatically improved over time, and the median survival after first-line chemoimmunotherapy now exceeds 18 years. But researchers have noted a remarkably consistent 20% rate of early relapse across numerous forms of treatment and varied study populations. Until now, the clinical significance of early relapse and its impact on overall survival has not been explored, said Dr. Carla Casulo of the University of Rochester, New York, and her associates.

They examined this issue using data from a national cohort of patients with newly diagnosed follicular lymphoma, focusing on 588 patients with stage II, III, or IV disease who were treated using first-line rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). A total of 19% of these patients relapsed within 24 months of diagnosis. Median follow-up was 7 years. With early disease progression, overall survival was only 68% at 2 years and only 50% at 5 years, compared with 97% and 90%, respectively, among patients who didn’t have early disease progression. Early progression was associated with markedly reduced survival, with a hazard ratio of 7.17.

To verify their findings in a separate cohort, Dr. Casulo and her associates assessed survival in 147 similar patients participating in a different study who were followed for a mean of 5.5 years. A total of 26% of this cohort had early relapse after receiving a variety of first-line chemoimmunotherapy regimens. With early disease progression, overall survival was only 64% at 2 years and only 34% at 5 years, compared with 98% and 94%, respectively, among patients who didn’t have early progression. Again, early progression was associated with markedly reduced survival, with an HR of 20.0 (J. Clin. Oncol. 2015 June 29 [doi: 10.1200/JCO.2014.59.7534]).

These two studies confirm that patients with follicular lymphoma who relapse within 2 years constitute a distinct subgroup at very high risk of death. “Given their poor prognosis, consideration of aggressive second-line treatments, including possibly autologous stem-cell transplantation, seem reasonable,” the investigators said.

Patients with follicular lymphoma who relapse within 2 years of receiving R-CHOP chemoimmunotherapy are at high risk of death, unlike those who do not relapse early, according to a report published online in Journal of Clinical Oncology.

Survival in follicular lymphoma, the second most common non-Hodgkin lymphoma in the United States, has dramatically improved over time, and the median survival after first-line chemoimmunotherapy now exceeds 18 years. But researchers have noted a remarkably consistent 20% rate of early relapse across numerous forms of treatment and varied study populations. Until now, the clinical significance of early relapse and its impact on overall survival has not been explored, said Dr. Carla Casulo of the University of Rochester, New York, and her associates.

They examined this issue using data from a national cohort of patients with newly diagnosed follicular lymphoma, focusing on 588 patients with stage II, III, or IV disease who were treated using first-line rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). A total of 19% of these patients relapsed within 24 months of diagnosis. Median follow-up was 7 years. With early disease progression, overall survival was only 68% at 2 years and only 50% at 5 years, compared with 97% and 90%, respectively, among patients who didn’t have early disease progression. Early progression was associated with markedly reduced survival, with a hazard ratio of 7.17.

To verify their findings in a separate cohort, Dr. Casulo and her associates assessed survival in 147 similar patients participating in a different study who were followed for a mean of 5.5 years. A total of 26% of this cohort had early relapse after receiving a variety of first-line chemoimmunotherapy regimens. With early disease progression, overall survival was only 64% at 2 years and only 34% at 5 years, compared with 98% and 94%, respectively, among patients who didn’t have early progression. Again, early progression was associated with markedly reduced survival, with an HR of 20.0 (J. Clin. Oncol. 2015 June 29 [doi: 10.1200/JCO.2014.59.7534]).

These two studies confirm that patients with follicular lymphoma who relapse within 2 years constitute a distinct subgroup at very high risk of death. “Given their poor prognosis, consideration of aggressive second-line treatments, including possibly autologous stem-cell transplantation, seem reasonable,” the investigators said.