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Combo produces responses in R/R Ph+ ALL
ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.
Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).
He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.
The patients received inotuzumab ozogamicin at 0.8 mg/m2 on day 1, 0.5 mg/m2 on day 8, and 0.5 mg/m2 on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m2 once every 4 weeks for subsequent cycles. Six cycles were planned.
Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).
The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.
The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.
Response and survival
The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.
All responses occurred among the patients with ALL.
Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.
The median duration of response was 8.8 months.
Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.
The median overall survival was 10.7 months.
“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”
Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen. 
*Data in the presentation differ from the abstract.
ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.
Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).
He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.
The patients received inotuzumab ozogamicin at 0.8 mg/m2 on day 1, 0.5 mg/m2 on day 8, and 0.5 mg/m2 on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m2 once every 4 weeks for subsequent cycles. Six cycles were planned.
Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).
The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.
The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.
Response and survival
The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.
All responses occurred among the patients with ALL.
Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.
The median duration of response was 8.8 months.
Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.
The median overall survival was 10.7 months.
“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”
Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.
*Data in the presentation differ from the abstract.
ATLANTA—A 2-drug combination has produced a high response rate in a small trial of patients with relapsed/refractory (R/R), Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
The combination, inotuzumab ozogamicin and bosutinib, produced an overall response rate of 81% in this ongoing, phase 1/2 trial.
Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center in Houston, presented phase 1 results from the study at the 2017 ASH Annual Meeting (abstract 143*).
He reported results in 16 patients, 14 with R/R, Ph+ ALL and 2 with chronic myeloid leukemia in lymphoid blast phase.
The patients received inotuzumab ozogamicin at 0.8 mg/m2 on day 1, 0.5 mg/m2 on day 8, and 0.5 mg/m2 on day 15 of cycle 1. Patients who achieved a response received inotuzumab ozogamicin at 1 mg/m2 once every 4 weeks for subsequent cycles. Six cycles were planned.
Patients also received bosutinib at 300 mg, 400 mg, or 500 mg once a day for 4-week cycles. The median number of cycles was 2.5 (range, 1-8).
The maximum-tolerated dose has not been established, but there were 2 dose-limiting toxicities (DLTs). One DLT occurred with the 400 mg dose of bosutinib, and 1 occurred with the 500 mg dose. Both DLTs were grade 3 skin rash.
The investigators are continuing accrual with the 500 mg dose of bosutinib for the phase 2 portion of the trial, with 22 additional patients.
Response and survival
The overall response rate was 81% (n=13). This included a complete response (CR) in 8 patients, a CR with incomplete blood count recovery in 3 patients, and a CR with incomplete platelet recovery in 2 patients.
All responses occurred among the patients with ALL.
Twelve responders achieved complete cytogenetic remission, 11 achieved a major molecular response, 8 achieved a complete molecular response, and 9 were negative by flow cytometry.
The median duration of response was 8.8 months.
Of the 13 responders, 6 went on to receive an allogeneic stem cell transplant. Five of these patients are still alive, but 1 died from relapse.
The median overall survival was 10.7 months.
“These data suggest the tolerability and efficacy of inotuzumab ozogamicin and bosutinib in R/R Ph+ ALL,” Dr Jain said. “And we are looking forward to the next phase of this study.”
Dr Jain disclosed receiving research funding from Celgene, Verastem, BMS, Incyte, Pharmacyclics, ADC Therapeutics, Genentech, AbbVie, Pfizer, Astra Zeneca, Janssen, Cellectis, and Seattle Genetics. He disclosed membership on boards of directors/advisory committees for Verastem, Servier, Novimmune, Pharmacyclics, Novartis, ADC Therapeutics, AbbVie, Pfizer, Adaptive Biotechnologies, and Janssen.
*Data in the presentation differ from the abstract.
Combo shows promise for elderly/unfit ALL patients
ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.
More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.
“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.
Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).
The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.
The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.
Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.
Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.
Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.
The median follow-up was 17.2 months.
Results
Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.
The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.
Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.
One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.
The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.
“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.
He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.
Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.
Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).
Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).
Dr Martinelli reported no disclosures.
*Data in the presentation differ from the abstract.
ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.
More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.
“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.
Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).
The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.
The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.
Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.
Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.
Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.
The median follow-up was 17.2 months.
Results
Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.
The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.
Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.
One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.
The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.
“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.
He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.
Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.
Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).
Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).
Dr Martinelli reported no disclosures.
*Data in the presentation differ from the abstract.
ATLANTA—Results of a phase 2 trial suggest treatment with ponatinib and steroids is feasible for patients with acute lymphoblastic leukemia (ALL) who are elderly and/or unfit for intensive chemotherapy and stem cell transplant.
More than 90% of patients who received this combination had a complete hematologic response at 24 weeks, and the treatment was considered well-tolerated.
“Ponatinib plus steroids is safe and effective in this fragile patient population, which is in urgent need of better therapeutic regimens,” said Giovanni Martinelli, MD, of the University of Bologna in Italy.
Dr Martinelli presented these findings at the 2017 ASH Annual Meeting (abstract 99*).
The trial (GIMEMA LAL 1811) was designed to evaluate whether steroids and ponatinib would be safe and effective in patients with newly diagnosed, Philadelphia chromosome-positive ALL who were older than 60 or ineligible for intensive chemotherapy and stem cell transplant.
The study included 42 such patients. Their median age was 68 (range, 27-85). Nine patients were younger than 60 and unfit.
Sixty-two percent of patients had the p190 fusion transcript, 10% had p210, and 29% had p190/210 transcripts.
Patients received oral ponatinib (45 mg/day) for 8 consecutive 6-week courses. They also received steroids from day -14 to day 29 of course 1.
Patients received intrathecal methotrexate, cytarabine, and dexamethasone every 28 days for central nervous system (CNS) disease prophylaxis. If they were positive for CNS disease at diagnosis, patients received intrathecal therapy twice a week until complete remission.
The median follow-up was 17.2 months.
Results
Thirty-nine patients received steroid pretreatment, and 14 of them had a reduction in circulating blasts of 75% or more before starting ponatinib.
The study’s primary endpoint was complete hematologic response, which occurred in 95.2% of patients at 6 weeks and 90.5% at 24 weeks.
Based on test sensitivity of at least 10,000 ABL molecules, 60.6% of evaluable patients (20/33) had a complete molecular response at 24 weeks.
One patient with relapse had evidence of T315L mutations, which correlates with ponatinib resistance. No other mutations were detected in patients with relapse.
The overall survival rate was 97.6% at 6 months and 87.5% at 1 year.
“The fast and deep reduction of the disease burden in the majority of patients, the ability of ponatinib to prevent the emergence of clones harboring BCR-ABL mutations, and the synthetic lethality with steroids on the BCR-ABL, FLT3, HCK, CDK6, MCL1 pathway most likely explain the therapeutic effectiveness of this regimen,” Dr Martinelli said.
He also said steroids and ponatinib were well-tolerated, with 15 patients continuing treatment at 24 weeks.
Of 75 adverse events (AEs), 36 were related to ponatinib. There were 26 serious AEs, and 13 of them were related to ponatinib.
Serious cardiovascular AEs included arterial disorders (n=3), embolism (n=2), acute coronary syndrome (n=2), acute myocardial infarction (n=1), cardiac failure (n=1), pericardial effusion (n=1), and ischemia (n=1).
Ten deaths were reported. The causes were identified as progression (n=4), cardiovascular disease (n=3), toxicity (n=1), toxicity and progression (n=1), and unknown cause (n=1).
Dr Martinelli reported no disclosures.
*Data in the presentation differ from the abstract.
Cell-free DNA mutational analysis in AITL
SAN FRANCISCO—An exploratory study suggests cell-free DNA from peripheral blood may be a viable alternative to tumor DNA for mutational profiling in angioimmunoblastic T-cell lymphoma (AITL).
Investigators sequenced cell-free DNA and tumor DNA collected from 13 patients with AITL and found that, in 85% of cases, there was concordance between the tumor mutational profile and the cell-free DNA mutational profile.
“The cell-free DNA mutational analysis seems to mirror the mutational analysis of the tumor in the majority of cases,” said Neha Mehta-Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
“This may be particularly interesting when we don’t have very much tumor DNA available for sequencing, as occurs frequently in this patient population.”
Dr Mehta-Shah presented these findings at the 9th Annual T-cell Lymphoma Forum.
She said the primary objective of this study was to evaluate whether somatic mutation analysis of cell-free DNA for IDH2 correlates with tumor mutational profiling for IDH2.
The secondary objective was to evaluate whether somatic mutational analysis of cell-free DNA mirrors the mutational profile of the tumor.
So Dr Mehta-Shah and her colleagues sequenced various samples from 14 patients with AITL (4 who were newly diagnosed and 10 with relapsed disease).
The investigators compared cell-free DNA obtained from peripheral blood samples with genomic DNA obtained from primary tumor biopsies and with DNA from peripheral blood mononuclear cells (for germline comparison). One of the 14 patients didn’t have tumor tissue available, so 13 patients were included in the analysis.
The team performed targeted next-generation sequencing using Memorial Sloan Kettering Cancer Center’s IMPACT platform, which sequences 410 genes known to be recurrently mutated in cancer.
The investigators observed concordance between the tumor mutational profile and the cell-free DNA profile in 85% of cases (11/13).
Identical alterations in TET2, RHOA, IDH2, DNMT3A, and ROS1 were detected in cell-free DNA from peripheral blood and tumor genomic DNA, with a similar variant allele frequency.
On the other hand, mutational analysis of cell-free DNA obtained from urine samples from 2 of the patients did not correlate with somatic mutations from tumor DNA.
This research also revealed that some samples had multiple mutations in TET2, which are indicative of subclonal populations.
And sequential samples from 2 patients, collected at the start of salvage therapy and at subsequent relapse, showed the disappearance of mutations in RHOA, TET2, and IDH2. This observation has been attributed to clonal evolution and/or changes in overall disease burden. 
SAN FRANCISCO—An exploratory study suggests cell-free DNA from peripheral blood may be a viable alternative to tumor DNA for mutational profiling in angioimmunoblastic T-cell lymphoma (AITL).
Investigators sequenced cell-free DNA and tumor DNA collected from 13 patients with AITL and found that, in 85% of cases, there was concordance between the tumor mutational profile and the cell-free DNA mutational profile.
“The cell-free DNA mutational analysis seems to mirror the mutational analysis of the tumor in the majority of cases,” said Neha Mehta-Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
“This may be particularly interesting when we don’t have very much tumor DNA available for sequencing, as occurs frequently in this patient population.”
Dr Mehta-Shah presented these findings at the 9th Annual T-cell Lymphoma Forum.
She said the primary objective of this study was to evaluate whether somatic mutation analysis of cell-free DNA for IDH2 correlates with tumor mutational profiling for IDH2.
The secondary objective was to evaluate whether somatic mutational analysis of cell-free DNA mirrors the mutational profile of the tumor.
So Dr Mehta-Shah and her colleagues sequenced various samples from 14 patients with AITL (4 who were newly diagnosed and 10 with relapsed disease).
The investigators compared cell-free DNA obtained from peripheral blood samples with genomic DNA obtained from primary tumor biopsies and with DNA from peripheral blood mononuclear cells (for germline comparison). One of the 14 patients didn’t have tumor tissue available, so 13 patients were included in the analysis.
The team performed targeted next-generation sequencing using Memorial Sloan Kettering Cancer Center’s IMPACT platform, which sequences 410 genes known to be recurrently mutated in cancer.
The investigators observed concordance between the tumor mutational profile and the cell-free DNA profile in 85% of cases (11/13).
Identical alterations in TET2, RHOA, IDH2, DNMT3A, and ROS1 were detected in cell-free DNA from peripheral blood and tumor genomic DNA, with a similar variant allele frequency.
On the other hand, mutational analysis of cell-free DNA obtained from urine samples from 2 of the patients did not correlate with somatic mutations from tumor DNA.
This research also revealed that some samples had multiple mutations in TET2, which are indicative of subclonal populations.
And sequential samples from 2 patients, collected at the start of salvage therapy and at subsequent relapse, showed the disappearance of mutations in RHOA, TET2, and IDH2. This observation has been attributed to clonal evolution and/or changes in overall disease burden.
SAN FRANCISCO—An exploratory study suggests cell-free DNA from peripheral blood may be a viable alternative to tumor DNA for mutational profiling in angioimmunoblastic T-cell lymphoma (AITL).
Investigators sequenced cell-free DNA and tumor DNA collected from 13 patients with AITL and found that, in 85% of cases, there was concordance between the tumor mutational profile and the cell-free DNA mutational profile.
“The cell-free DNA mutational analysis seems to mirror the mutational analysis of the tumor in the majority of cases,” said Neha Mehta-Shah, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.
“This may be particularly interesting when we don’t have very much tumor DNA available for sequencing, as occurs frequently in this patient population.”
Dr Mehta-Shah presented these findings at the 9th Annual T-cell Lymphoma Forum.
She said the primary objective of this study was to evaluate whether somatic mutation analysis of cell-free DNA for IDH2 correlates with tumor mutational profiling for IDH2.
The secondary objective was to evaluate whether somatic mutational analysis of cell-free DNA mirrors the mutational profile of the tumor.
So Dr Mehta-Shah and her colleagues sequenced various samples from 14 patients with AITL (4 who were newly diagnosed and 10 with relapsed disease).
The investigators compared cell-free DNA obtained from peripheral blood samples with genomic DNA obtained from primary tumor biopsies and with DNA from peripheral blood mononuclear cells (for germline comparison). One of the 14 patients didn’t have tumor tissue available, so 13 patients were included in the analysis.
The team performed targeted next-generation sequencing using Memorial Sloan Kettering Cancer Center’s IMPACT platform, which sequences 410 genes known to be recurrently mutated in cancer.
The investigators observed concordance between the tumor mutational profile and the cell-free DNA profile in 85% of cases (11/13).
Identical alterations in TET2, RHOA, IDH2, DNMT3A, and ROS1 were detected in cell-free DNA from peripheral blood and tumor genomic DNA, with a similar variant allele frequency.
On the other hand, mutational analysis of cell-free DNA obtained from urine samples from 2 of the patients did not correlate with somatic mutations from tumor DNA.
This research also revealed that some samples had multiple mutations in TET2, which are indicative of subclonal populations.
And sequential samples from 2 patients, collected at the start of salvage therapy and at subsequent relapse, showed the disappearance of mutations in RHOA, TET2, and IDH2. This observation has been attributed to clonal evolution and/or changes in overall disease burden.
Pathogenesis of breast-implant-associated ALCL
SAN FRANCISCO—A small study suggests an abnormal immune response characterized by the production of interleukin-13 (IL-13) underlies the pathogenesis of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
The immune response appears to be directed toward bacterial antigens on the surface of the breast implants.
Marshall E. Kadin, MD, of Roger Williams Medical Center in Providence, Rhode Island, presented these findings at the 9th Annual T-cell Lymphoma Forum.
Dr Kadin noted that BIA-ALCL is a rare type of CD30+ T-cell ALCL that has been reported in more than 200 women worldwide.
Although a cause-and-effect relationship between breast implants and BIA-ALCL has been suggested, the underlying pathogenesis of this malignancy is unclear.
A bacterial biofilm containing gram-negative bacilli has been detected in breast implants from patients with BIA-ALCL.
Therefore, Dr Kadin and his colleagues hypothesized that an immune response toward the bacterial antigens may mediate the pathogenesis of BIA-ALCL.
The researchers studied 13 clinical samples of breast implant capsules and regional lymph nodes from 4 patients with BIA-ALCL, 7 patients with systemic ALCL, and 1 patient with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).
Immunohistochemistry was used to determine the presence of IL-13, IL-4, GATA3, and immunoglobulin E (IgE) in these samples.
All clinical samples of anaplastic cells from breast implant capsules tested positive for the presence of IL-13 (13/13). GATA3 was expressed in most anaplastic cell samples (12/13), and IL-4 expression was found in some anaplastic cell samples (6/13). IL-13 and GATA3 expression were observed in some intra-capsular small lymphocytes.
While IL-13 was also detected in BIA-ALCL cell lines, it was not found in 4 of the 7 systemic ALCL cases or the PTCL-NOS case.
Dr Kadin said the lack of IL-13 receptor expression in BIA-ALCL cell lines suggests that IL-13 is not an autocrine growth factor for BIA-ALCL, and its expression is most likely associated with an allergic immune response.
IL-13 is known to induce immunoglobulin class switching in plasma cells to produce IgE. H&E and Giemsa staining of the BIA-ALCL tumor tissue and involved regional lymph nodes revealed IgE and eosinophils on the surface of mast cells and follicular dendritic cells.
Taken together, these data point to an allergic reaction in breast implant capsules of BIA-ALCL.
Dr Kadin was hopeful that these findings could be extrapolated to prevent BIA-ALCL by identifying individuals at higher risk for developing the disease.
The next step for this research is to decipher the role of bacterial antigens in mediating the immune response and whether women who develop BIA-ALCL have a significant increase in other atopic conditions.
SAN FRANCISCO—A small study suggests an abnormal immune response characterized by the production of interleukin-13 (IL-13) underlies the pathogenesis of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
The immune response appears to be directed toward bacterial antigens on the surface of the breast implants.
Marshall E. Kadin, MD, of Roger Williams Medical Center in Providence, Rhode Island, presented these findings at the 9th Annual T-cell Lymphoma Forum.
Dr Kadin noted that BIA-ALCL is a rare type of CD30+ T-cell ALCL that has been reported in more than 200 women worldwide.
Although a cause-and-effect relationship between breast implants and BIA-ALCL has been suggested, the underlying pathogenesis of this malignancy is unclear.
A bacterial biofilm containing gram-negative bacilli has been detected in breast implants from patients with BIA-ALCL.
Therefore, Dr Kadin and his colleagues hypothesized that an immune response toward the bacterial antigens may mediate the pathogenesis of BIA-ALCL.
The researchers studied 13 clinical samples of breast implant capsules and regional lymph nodes from 4 patients with BIA-ALCL, 7 patients with systemic ALCL, and 1 patient with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).
Immunohistochemistry was used to determine the presence of IL-13, IL-4, GATA3, and immunoglobulin E (IgE) in these samples.
All clinical samples of anaplastic cells from breast implant capsules tested positive for the presence of IL-13 (13/13). GATA3 was expressed in most anaplastic cell samples (12/13), and IL-4 expression was found in some anaplastic cell samples (6/13). IL-13 and GATA3 expression were observed in some intra-capsular small lymphocytes.
While IL-13 was also detected in BIA-ALCL cell lines, it was not found in 4 of the 7 systemic ALCL cases or the PTCL-NOS case.
Dr Kadin said the lack of IL-13 receptor expression in BIA-ALCL cell lines suggests that IL-13 is not an autocrine growth factor for BIA-ALCL, and its expression is most likely associated with an allergic immune response.
IL-13 is known to induce immunoglobulin class switching in plasma cells to produce IgE. H&E and Giemsa staining of the BIA-ALCL tumor tissue and involved regional lymph nodes revealed IgE and eosinophils on the surface of mast cells and follicular dendritic cells.
Taken together, these data point to an allergic reaction in breast implant capsules of BIA-ALCL.
Dr Kadin was hopeful that these findings could be extrapolated to prevent BIA-ALCL by identifying individuals at higher risk for developing the disease.
The next step for this research is to decipher the role of bacterial antigens in mediating the immune response and whether women who develop BIA-ALCL have a significant increase in other atopic conditions.
SAN FRANCISCO—A small study suggests an abnormal immune response characterized by the production of interleukin-13 (IL-13) underlies the pathogenesis of breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).
The immune response appears to be directed toward bacterial antigens on the surface of the breast implants.
Marshall E. Kadin, MD, of Roger Williams Medical Center in Providence, Rhode Island, presented these findings at the 9th Annual T-cell Lymphoma Forum.
Dr Kadin noted that BIA-ALCL is a rare type of CD30+ T-cell ALCL that has been reported in more than 200 women worldwide.
Although a cause-and-effect relationship between breast implants and BIA-ALCL has been suggested, the underlying pathogenesis of this malignancy is unclear.
A bacterial biofilm containing gram-negative bacilli has been detected in breast implants from patients with BIA-ALCL.
Therefore, Dr Kadin and his colleagues hypothesized that an immune response toward the bacterial antigens may mediate the pathogenesis of BIA-ALCL.
The researchers studied 13 clinical samples of breast implant capsules and regional lymph nodes from 4 patients with BIA-ALCL, 7 patients with systemic ALCL, and 1 patient with peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).
Immunohistochemistry was used to determine the presence of IL-13, IL-4, GATA3, and immunoglobulin E (IgE) in these samples.
All clinical samples of anaplastic cells from breast implant capsules tested positive for the presence of IL-13 (13/13). GATA3 was expressed in most anaplastic cell samples (12/13), and IL-4 expression was found in some anaplastic cell samples (6/13). IL-13 and GATA3 expression were observed in some intra-capsular small lymphocytes.
While IL-13 was also detected in BIA-ALCL cell lines, it was not found in 4 of the 7 systemic ALCL cases or the PTCL-NOS case.
Dr Kadin said the lack of IL-13 receptor expression in BIA-ALCL cell lines suggests that IL-13 is not an autocrine growth factor for BIA-ALCL, and its expression is most likely associated with an allergic immune response.
IL-13 is known to induce immunoglobulin class switching in plasma cells to produce IgE. H&E and Giemsa staining of the BIA-ALCL tumor tissue and involved regional lymph nodes revealed IgE and eosinophils on the surface of mast cells and follicular dendritic cells.
Taken together, these data point to an allergic reaction in breast implant capsules of BIA-ALCL.
Dr Kadin was hopeful that these findings could be extrapolated to prevent BIA-ALCL by identifying individuals at higher risk for developing the disease.
The next step for this research is to decipher the role of bacterial antigens in mediating the immune response and whether women who develop BIA-ALCL have a significant increase in other atopic conditions.
Study sheds light on genetic landscape of HSTL
SAN FRANCISCO—Researchers say they have identified new driver genes and oncogenic pathways in hepatosplenic T-cell lymphoma (HSTL).
The team found that SETD2, a known tumor suppressor, was the most frequently silenced gene in HSTL.
The researchers also found evidence suggesting the JAK-STAT and PI3K pathways could be therapeutic targets in HSTL.
Sandeep Dave, MD, of Duke University in Durham, North Carolina, presented these findings at the 9th Annual T-cell Lymphoma Forum. Results from this research were also published in Cancer Discovery.
The researchers collected complete clinical data on 68 HSTL cases, including 20 with normal DNA. The team performed whole-genome sequencing, bioinformatics analysis, and biological characterization of these cases.
“This is the largest group of HSTL cases ever described, and the data implicate new driver genes and oncogenic pathways for the first time in HSTL,” Dr Dave said.
The data revealed that the most commonly mutated group of genes in HSTL are chromatin modifiers (SETD2, INO80, ARID1B, TET3, and SMARCA2) and signaling pathway genes (STAT5B, STAT3, and PIK3CD). Among these, STAT3, PIK3CD, and SETD2 showed the highest proportion of clonal events.
On the other hand, mutations in EZH2, KRAS, and TP53 were less frequently observed.
Common genetic abnormalities in HSTL include copy number alterations in chromosome 7, trisomy 8, loss of 10p, and gain of 1q.
A comparison of the frequencies of recurrently mutated genes in HSTL with other lymphomas demonstrated the genetically distinct profile of HSTL, wherein mutations in SETD2, INO80, TET3, and STAT5B occurred exclusively in HSTL.
SETD2, a histone lysine methyltransferase and a known tumor suppressor, was identified as the most frequently silenced gene in HSTL.
So the researchers investigated the biological effects of SETD2 loss in HSTL cells and a knockout mouse model.
While loss of SETD2 in HSTL cells resulted in increased cell proliferation, in vivo knockdown of SETD2 led to expansion of γ-δ T cells and a reduction in α-β T cells. A majority of HSTLs are known to arise predominantly from γ-δ T cells.
“These results implicate SETD2 in HSTL oncogenesis and T-cell development,” Dr Dave said.
He and his colleagues also found that constitutive activation of the JAK-STAT and PI3K pathways in HSTL cells was associated with increased proliferation, and inhibition of these pathways led to reduced survival of HSTL cells. This suggests that agents targeting these pathways might be effective in treating HSTL.
SAN FRANCISCO—Researchers say they have identified new driver genes and oncogenic pathways in hepatosplenic T-cell lymphoma (HSTL).
The team found that SETD2, a known tumor suppressor, was the most frequently silenced gene in HSTL.
The researchers also found evidence suggesting the JAK-STAT and PI3K pathways could be therapeutic targets in HSTL.
Sandeep Dave, MD, of Duke University in Durham, North Carolina, presented these findings at the 9th Annual T-cell Lymphoma Forum. Results from this research were also published in Cancer Discovery.
The researchers collected complete clinical data on 68 HSTL cases, including 20 with normal DNA. The team performed whole-genome sequencing, bioinformatics analysis, and biological characterization of these cases.
“This is the largest group of HSTL cases ever described, and the data implicate new driver genes and oncogenic pathways for the first time in HSTL,” Dr Dave said.
The data revealed that the most commonly mutated group of genes in HSTL are chromatin modifiers (SETD2, INO80, ARID1B, TET3, and SMARCA2) and signaling pathway genes (STAT5B, STAT3, and PIK3CD). Among these, STAT3, PIK3CD, and SETD2 showed the highest proportion of clonal events.
On the other hand, mutations in EZH2, KRAS, and TP53 were less frequently observed.
Common genetic abnormalities in HSTL include copy number alterations in chromosome 7, trisomy 8, loss of 10p, and gain of 1q.
A comparison of the frequencies of recurrently mutated genes in HSTL with other lymphomas demonstrated the genetically distinct profile of HSTL, wherein mutations in SETD2, INO80, TET3, and STAT5B occurred exclusively in HSTL.
SETD2, a histone lysine methyltransferase and a known tumor suppressor, was identified as the most frequently silenced gene in HSTL.
So the researchers investigated the biological effects of SETD2 loss in HSTL cells and a knockout mouse model.
While loss of SETD2 in HSTL cells resulted in increased cell proliferation, in vivo knockdown of SETD2 led to expansion of γ-δ T cells and a reduction in α-β T cells. A majority of HSTLs are known to arise predominantly from γ-δ T cells.
“These results implicate SETD2 in HSTL oncogenesis and T-cell development,” Dr Dave said.
He and his colleagues also found that constitutive activation of the JAK-STAT and PI3K pathways in HSTL cells was associated with increased proliferation, and inhibition of these pathways led to reduced survival of HSTL cells. This suggests that agents targeting these pathways might be effective in treating HSTL.
SAN FRANCISCO—Researchers say they have identified new driver genes and oncogenic pathways in hepatosplenic T-cell lymphoma (HSTL).
The team found that SETD2, a known tumor suppressor, was the most frequently silenced gene in HSTL.
The researchers also found evidence suggesting the JAK-STAT and PI3K pathways could be therapeutic targets in HSTL.
Sandeep Dave, MD, of Duke University in Durham, North Carolina, presented these findings at the 9th Annual T-cell Lymphoma Forum. Results from this research were also published in Cancer Discovery.
The researchers collected complete clinical data on 68 HSTL cases, including 20 with normal DNA. The team performed whole-genome sequencing, bioinformatics analysis, and biological characterization of these cases.
“This is the largest group of HSTL cases ever described, and the data implicate new driver genes and oncogenic pathways for the first time in HSTL,” Dr Dave said.
The data revealed that the most commonly mutated group of genes in HSTL are chromatin modifiers (SETD2, INO80, ARID1B, TET3, and SMARCA2) and signaling pathway genes (STAT5B, STAT3, and PIK3CD). Among these, STAT3, PIK3CD, and SETD2 showed the highest proportion of clonal events.
On the other hand, mutations in EZH2, KRAS, and TP53 were less frequently observed.
Common genetic abnormalities in HSTL include copy number alterations in chromosome 7, trisomy 8, loss of 10p, and gain of 1q.
A comparison of the frequencies of recurrently mutated genes in HSTL with other lymphomas demonstrated the genetically distinct profile of HSTL, wherein mutations in SETD2, INO80, TET3, and STAT5B occurred exclusively in HSTL.
SETD2, a histone lysine methyltransferase and a known tumor suppressor, was identified as the most frequently silenced gene in HSTL.
So the researchers investigated the biological effects of SETD2 loss in HSTL cells and a knockout mouse model.
While loss of SETD2 in HSTL cells resulted in increased cell proliferation, in vivo knockdown of SETD2 led to expansion of γ-δ T cells and a reduction in α-β T cells. A majority of HSTLs are known to arise predominantly from γ-δ T cells.
“These results implicate SETD2 in HSTL oncogenesis and T-cell development,” Dr Dave said.
He and his colleagues also found that constitutive activation of the JAK-STAT and PI3K pathways in HSTL cells was associated with increased proliferation, and inhibition of these pathways led to reduced survival of HSTL cells. This suggests that agents targeting these pathways might be effective in treating HSTL.
Consortium to undertake longitudinal study of acquired TTP
Image by Erhabor Osaro
SAN DIEGO—The US Thrombotic Microangiopathies (USTMA) Consortium is planning a longitudinal study to identify biomarkers of relapse and neurocognitive dysfunction in acquired thrombotic thrombocytopenic purpura (TTP).
Earlier studies suggested that ADAMTS13 activity during remission has
limited utility in estimating relapse risk, and cognitive dysfunction
observed in TTP appears to be progressive and independent of relapses.
However, these studies were small with minimal longitudinal data.
Now, the USTMA Consortium, with 13 large referral centers for thrombotic microangiopathies (TMAs) in the US, is providing “the infrastructure for larger US studies in TTP with the goal of improving outcomes in TMAs,” said Marshall A. Mazepa, MD, of the University of Minnesota in Minneapolis.
He described the efforts of the consortium and its plans to conduct a long-term study at the first TTP-TMA Workshop, which took place immediately before the 2016 ASH Annual Meeting.
Dr Mazepa said the objective of the study is to identify biomarkers that
predict the danger period for neurocognitive dysfunction and relapse.
“Hematologists usually do not realize the
neurocognitive dysfunction among patients with TTP, and it is important
that they [hematologists] talk to neurologists,” said Spero Cataland, MD, an organizer of the TTP-TMA Workshop from The Ohio State University in
Columbus.
“This study will be crucial in
improving our understanding of this issue.”
The consortium plans to study 100 TTP patients in remission for 3 years.
Every
3 months, patients will complete neuropsychologic testing, and
investigators will evaluate patients’ end-organ ischemic biomarkers,
ADAMTS13 activity, ultra-large von Willebrand factor levels, and
complement activation biomarkers.
In addition to this study, the USTMA Consortium is participating in the phase 3 HERCULES study of caplacizumab for acquired TTP.
Caplacizumab, which is being developed by Ablynx, was previously evaluated for acquired TTP in the phase 2 TITAN study.
The phase 3 study is a double-blind, placebo-controlled trial designed to determine whether neurocognitive function can be preserved with caplacizumab intervention.
Investigators intend to enroll 92 patients at clinical sites in 17 countries. Recruitment is expected to be complete by the end of 2017.
In closing, Dr Mazepa invited interested clinicians to join the USTMA Consortium by contacting him (mmazepa@umn.edu) or Dr Cataland (spero.cataland@osumc.edu).
Image by Erhabor Osaro
SAN DIEGO—The US Thrombotic Microangiopathies (USTMA) Consortium is planning a longitudinal study to identify biomarkers of relapse and neurocognitive dysfunction in acquired thrombotic thrombocytopenic purpura (TTP).
Earlier studies suggested that ADAMTS13 activity during remission has
limited utility in estimating relapse risk, and cognitive dysfunction
observed in TTP appears to be progressive and independent of relapses.
However, these studies were small with minimal longitudinal data.
Now, the USTMA Consortium, with 13 large referral centers for thrombotic microangiopathies (TMAs) in the US, is providing “the infrastructure for larger US studies in TTP with the goal of improving outcomes in TMAs,” said Marshall A. Mazepa, MD, of the University of Minnesota in Minneapolis.
He described the efforts of the consortium and its plans to conduct a long-term study at the first TTP-TMA Workshop, which took place immediately before the 2016 ASH Annual Meeting.
Dr Mazepa said the objective of the study is to identify biomarkers that
predict the danger period for neurocognitive dysfunction and relapse.
“Hematologists usually do not realize the
neurocognitive dysfunction among patients with TTP, and it is important
that they [hematologists] talk to neurologists,” said Spero Cataland, MD, an organizer of the TTP-TMA Workshop from The Ohio State University in
Columbus.
“This study will be crucial in
improving our understanding of this issue.”
The consortium plans to study 100 TTP patients in remission for 3 years.
Every
3 months, patients will complete neuropsychologic testing, and
investigators will evaluate patients’ end-organ ischemic biomarkers,
ADAMTS13 activity, ultra-large von Willebrand factor levels, and
complement activation biomarkers.
In addition to this study, the USTMA Consortium is participating in the phase 3 HERCULES study of caplacizumab for acquired TTP.
Caplacizumab, which is being developed by Ablynx, was previously evaluated for acquired TTP in the phase 2 TITAN study.
The phase 3 study is a double-blind, placebo-controlled trial designed to determine whether neurocognitive function can be preserved with caplacizumab intervention.
Investigators intend to enroll 92 patients at clinical sites in 17 countries. Recruitment is expected to be complete by the end of 2017.
In closing, Dr Mazepa invited interested clinicians to join the USTMA Consortium by contacting him (mmazepa@umn.edu) or Dr Cataland (spero.cataland@osumc.edu).
Image by Erhabor Osaro
SAN DIEGO—The US Thrombotic Microangiopathies (USTMA) Consortium is planning a longitudinal study to identify biomarkers of relapse and neurocognitive dysfunction in acquired thrombotic thrombocytopenic purpura (TTP).
Earlier studies suggested that ADAMTS13 activity during remission has
limited utility in estimating relapse risk, and cognitive dysfunction
observed in TTP appears to be progressive and independent of relapses.
However, these studies were small with minimal longitudinal data.
Now, the USTMA Consortium, with 13 large referral centers for thrombotic microangiopathies (TMAs) in the US, is providing “the infrastructure for larger US studies in TTP with the goal of improving outcomes in TMAs,” said Marshall A. Mazepa, MD, of the University of Minnesota in Minneapolis.
He described the efforts of the consortium and its plans to conduct a long-term study at the first TTP-TMA Workshop, which took place immediately before the 2016 ASH Annual Meeting.
Dr Mazepa said the objective of the study is to identify biomarkers that
predict the danger period for neurocognitive dysfunction and relapse.
“Hematologists usually do not realize the
neurocognitive dysfunction among patients with TTP, and it is important
that they [hematologists] talk to neurologists,” said Spero Cataland, MD, an organizer of the TTP-TMA Workshop from The Ohio State University in
Columbus.
“This study will be crucial in
improving our understanding of this issue.”
The consortium plans to study 100 TTP patients in remission for 3 years.
Every
3 months, patients will complete neuropsychologic testing, and
investigators will evaluate patients’ end-organ ischemic biomarkers,
ADAMTS13 activity, ultra-large von Willebrand factor levels, and
complement activation biomarkers.
In addition to this study, the USTMA Consortium is participating in the phase 3 HERCULES study of caplacizumab for acquired TTP.
Caplacizumab, which is being developed by Ablynx, was previously evaluated for acquired TTP in the phase 2 TITAN study.
The phase 3 study is a double-blind, placebo-controlled trial designed to determine whether neurocognitive function can be preserved with caplacizumab intervention.
Investigators intend to enroll 92 patients at clinical sites in 17 countries. Recruitment is expected to be complete by the end of 2017.
In closing, Dr Mazepa invited interested clinicians to join the USTMA Consortium by contacting him (mmazepa@umn.edu) or Dr Cataland (spero.cataland@osumc.edu).