Sharon Worcester

SALT LAKE CITY – KD025, an orally available Rho-associated coiled-coil kinase 2–selective inhibitor, is demonstrating encouraging activity and safety in patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2a clinical trial.

Initial results from the ongoing open-label trial known as KD025-208 showed that 11 of 17 patients (65%) and 11 of 16 patients (69%) enrolled in 200-mg daily and 200-mg twice-daily dose cohorts, respectively, had a clinical response with no reported treatment-related serious adverse events at any evaluation time point, Aleksandr Lazaryan, MD, PhD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Sharon Worcester/Frontline Medical News

In cohort 1, four patients went off the study because of cGVHD progression, and five withdrew, including two who experienced recurrence of their underlying hematologic malignancy. In cohort 2, 7 of the 16 patients experienced progression of cGVHD, he noted.

Patients in cohorts 1 and 2 had a median age of 52 years and had received at least 2 months of steroid treatment and no more than 3 prior lines of therapy. They were comparable with respect to baseline characteristics, including median time to and duration of GVHD, time from diagnosis to enrollment, median prednisone dose, and median number of prior therapies. They had involvement of various – and often multiple – organ systems: 58% had four or more systems affected at the time of enrollment, and 21% had five or more systems affected.

“This, in a way, reflects a real-life mix of the cGVHD population of patients, with some of those patients having advanced cGVHD,” said Dr. Lazaryan.

Responses were observed across all affected organ systems, with complete responses documented in the upper and lower gastrointestinal tracts. About 75% of patients in cohort 1 who had multiple organ systems involved at enrollment demonstrated responses in at least four organ systems.

Furthermore, the responses were rapid: 68% of responses occurred in the first 8 weeks of treatment and appeared durable, Dr. Lazaryan said, noting that 7 of the 17 patients in cohort 1 had sustained responses for more than 20 weeks, and 3 patients had sustained responses for more than 32 weeks.

“The durability data continue to mature in this trial,” he added.

The adverse events that occurred were consistent with what would be expected for the cGVHD patient population treated with steroids, he said, reporting that no patients discontinued treatment because of infection, no opportunistic or fungal infections have been reported to date, and no treatment-related serious adverse events were reported.

Steroid dose reductions were experienced by 40% and 26% of patients in cohorts 1 and 2, respectively. The dose reductions were achieved in both KD025 responders and nonresponders, he noted.

Overall, four patients (12%) were able to discontinue steroids, and 80% in both cohorts experienced reductions in background tacrolimus.

In addition, up to 65% of patients in cohort 1 achieved a greater than seven point reduction on the Lee cGVHD Symptom Scale, with both responders and nonresponders experiencing improvement on this endpoint.

Chronic GVHD remains a leading cause of post-transplant morbidity and mortality. KD025, which is currently in phase 2 development for inflammatory fibrotic disease, has been shown in preclinical models to down-regulate T helper 17 cells and T follicular helper cells while up-regulating anti-inflammatory regulatory T cells, thereby potentially correcting the immunological imbalance seen in cGVHD, Dr. Lazaryan said.

Analysis is ongoing in this study, including in a third cohort of patients treated with 200 mg of KD025 four times daily, which recently completed accrual. An expansion cohort, at a dose yet to be determined, will include approximately 40 patients, he noted.

The trial is sponsored by Kadmon. Dr. Lazaryan reported advisory board membership and consultancy for GLyPharma Therapeutic.

sworcester@frontlinemedcom.com

SOURCE: Lazaryan A et al. 2018 BMT Tandem Meetings, Abstract 38.

SALT LAKE CITY – KD025, an orally available Rho-associated coiled-coil kinase 2–selective inhibitor, is demonstrating encouraging activity and safety in patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2a clinical trial.

Initial results from the ongoing open-label trial known as KD025-208 showed that 11 of 17 patients (65%) and 11 of 16 patients (69%) enrolled in 200-mg daily and 200-mg twice-daily dose cohorts, respectively, had a clinical response with no reported treatment-related serious adverse events at any evaluation time point, Aleksandr Lazaryan, MD, PhD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Sharon Worcester/Frontline Medical News

In cohort 1, four patients went off the study because of cGVHD progression, and five withdrew, including two who experienced recurrence of their underlying hematologic malignancy. In cohort 2, 7 of the 16 patients experienced progression of cGVHD, he noted.

Patients in cohorts 1 and 2 had a median age of 52 years and had received at least 2 months of steroid treatment and no more than 3 prior lines of therapy. They were comparable with respect to baseline characteristics, including median time to and duration of GVHD, time from diagnosis to enrollment, median prednisone dose, and median number of prior therapies. They had involvement of various – and often multiple – organ systems: 58% had four or more systems affected at the time of enrollment, and 21% had five or more systems affected.

“This, in a way, reflects a real-life mix of the cGVHD population of patients, with some of those patients having advanced cGVHD,” said Dr. Lazaryan.

Responses were observed across all affected organ systems, with complete responses documented in the upper and lower gastrointestinal tracts. About 75% of patients in cohort 1 who had multiple organ systems involved at enrollment demonstrated responses in at least four organ systems.

Furthermore, the responses were rapid: 68% of responses occurred in the first 8 weeks of treatment and appeared durable, Dr. Lazaryan said, noting that 7 of the 17 patients in cohort 1 had sustained responses for more than 20 weeks, and 3 patients had sustained responses for more than 32 weeks.

“The durability data continue to mature in this trial,” he added.

The adverse events that occurred were consistent with what would be expected for the cGVHD patient population treated with steroids, he said, reporting that no patients discontinued treatment because of infection, no opportunistic or fungal infections have been reported to date, and no treatment-related serious adverse events were reported.

Steroid dose reductions were experienced by 40% and 26% of patients in cohorts 1 and 2, respectively. The dose reductions were achieved in both KD025 responders and nonresponders, he noted.

Overall, four patients (12%) were able to discontinue steroids, and 80% in both cohorts experienced reductions in background tacrolimus.

In addition, up to 65% of patients in cohort 1 achieved a greater than seven point reduction on the Lee cGVHD Symptom Scale, with both responders and nonresponders experiencing improvement on this endpoint.

Chronic GVHD remains a leading cause of post-transplant morbidity and mortality. KD025, which is currently in phase 2 development for inflammatory fibrotic disease, has been shown in preclinical models to down-regulate T helper 17 cells and T follicular helper cells while up-regulating anti-inflammatory regulatory T cells, thereby potentially correcting the immunological imbalance seen in cGVHD, Dr. Lazaryan said.

Analysis is ongoing in this study, including in a third cohort of patients treated with 200 mg of KD025 four times daily, which recently completed accrual. An expansion cohort, at a dose yet to be determined, will include approximately 40 patients, he noted.

The trial is sponsored by Kadmon. Dr. Lazaryan reported advisory board membership and consultancy for GLyPharma Therapeutic.

sworcester@frontlinemedcom.com

SOURCE: Lazaryan A et al. 2018 BMT Tandem Meetings, Abstract 38.

SALT LAKE CITY – KD025, an orally available Rho-associated coiled-coil kinase 2–selective inhibitor, is demonstrating encouraging activity and safety in patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2a clinical trial.

Initial results from the ongoing open-label trial known as KD025-208 showed that 11 of 17 patients (65%) and 11 of 16 patients (69%) enrolled in 200-mg daily and 200-mg twice-daily dose cohorts, respectively, had a clinical response with no reported treatment-related serious adverse events at any evaluation time point, Aleksandr Lazaryan, MD, PhD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Sharon Worcester/Frontline Medical News

In cohort 1, four patients went off the study because of cGVHD progression, and five withdrew, including two who experienced recurrence of their underlying hematologic malignancy. In cohort 2, 7 of the 16 patients experienced progression of cGVHD, he noted.

Patients in cohorts 1 and 2 had a median age of 52 years and had received at least 2 months of steroid treatment and no more than 3 prior lines of therapy. They were comparable with respect to baseline characteristics, including median time to and duration of GVHD, time from diagnosis to enrollment, median prednisone dose, and median number of prior therapies. They had involvement of various – and often multiple – organ systems: 58% had four or more systems affected at the time of enrollment, and 21% had five or more systems affected.

“This, in a way, reflects a real-life mix of the cGVHD population of patients, with some of those patients having advanced cGVHD,” said Dr. Lazaryan.

Responses were observed across all affected organ systems, with complete responses documented in the upper and lower gastrointestinal tracts. About 75% of patients in cohort 1 who had multiple organ systems involved at enrollment demonstrated responses in at least four organ systems.

Furthermore, the responses were rapid: 68% of responses occurred in the first 8 weeks of treatment and appeared durable, Dr. Lazaryan said, noting that 7 of the 17 patients in cohort 1 had sustained responses for more than 20 weeks, and 3 patients had sustained responses for more than 32 weeks.

“The durability data continue to mature in this trial,” he added.

The adverse events that occurred were consistent with what would be expected for the cGVHD patient population treated with steroids, he said, reporting that no patients discontinued treatment because of infection, no opportunistic or fungal infections have been reported to date, and no treatment-related serious adverse events were reported.

Steroid dose reductions were experienced by 40% and 26% of patients in cohorts 1 and 2, respectively. The dose reductions were achieved in both KD025 responders and nonresponders, he noted.

Overall, four patients (12%) were able to discontinue steroids, and 80% in both cohorts experienced reductions in background tacrolimus.

In addition, up to 65% of patients in cohort 1 achieved a greater than seven point reduction on the Lee cGVHD Symptom Scale, with both responders and nonresponders experiencing improvement on this endpoint.

Chronic GVHD remains a leading cause of post-transplant morbidity and mortality. KD025, which is currently in phase 2 development for inflammatory fibrotic disease, has been shown in preclinical models to down-regulate T helper 17 cells and T follicular helper cells while up-regulating anti-inflammatory regulatory T cells, thereby potentially correcting the immunological imbalance seen in cGVHD, Dr. Lazaryan said.

Analysis is ongoing in this study, including in a third cohort of patients treated with 200 mg of KD025 four times daily, which recently completed accrual. An expansion cohort, at a dose yet to be determined, will include approximately 40 patients, he noted.

The trial is sponsored by Kadmon. Dr. Lazaryan reported advisory board membership and consultancy for GLyPharma Therapeutic.

sworcester@frontlinemedcom.com

SOURCE: Lazaryan A et al. 2018 BMT Tandem Meetings, Abstract 38.

ATLANTA – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.

The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD, reported at the annual meeting of the American Society of Hematology.

Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.

The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.

sworcester@frontlinemedcom.com

ATLANTA – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.

The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD, reported at the annual meeting of the American Society of Hematology.

Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.

The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.

sworcester@frontlinemedcom.com

ATLANTA – Mitoxantrone, etoposide, and cytarabine (MEC) in combination with the second-generation proteasome inhibitor ixazomib was well tolerated and effective in a phase 1 expansion study of patients with relapsed or refractory acute myeloid leukemia.

The overall response rate in 30 patients enrolled in the study and treated with the novel combination was 53%; 11 patients had a complete response (CR), and 5 had a complete response with incomplete blood count recovery (CRi). The median overall survival was 4.9 months, Anjali S. Advani, MD, reported at the annual meeting of the American Society of Hematology.

Thirteen patients proceeded to allogeneic hematopoietic cell transplant (AHCT), and one received a donor lymphocyte infusion. Seven of these 14 patients are alive with a median follow-up of 14.5 months, said Dr. Advani of Taussig Cancer Institute, Cleveland Clinic.

The patients, who had a median age of 58 years (range of 18-70 years), were eligible for the study if they had relapsed/refractory acute myeloid leukemia (AML), adequate organ function, and cardiac ejection fraction of at least 45%. The median time from initial diagnosis to enrollment was 7.6 months.

sworcester@frontlinemedcom.com

SALT LAKE CITY – Scores of 3 or higher on the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) are associated with an increased risk of posttransplant mortality in certain patients undergoing allogeneic HCT for nonmalignant disease, according to findings from a review of more than 4,000 patients.

The exception was in patients undergoing HCT for hemoglobinopathies, Larisa Broglie, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The findings of the study, which is the largest to date to validate the usefulness of the HCT-CI for risk assessment in HCT patients with nonmalignant disease, have important implications for patient counseling and decision making, said Dr. Broglie of the Medical College of Wisconsin, Milwaukee.

Of 4,083 children and adults who underwent a first allogeneic HCT for a nonmalignant disease between 2007 and 2014 and who had sufficient follow-up (median, 39 months), 61% had an HCT-CI score of 0, 20% had a score of 1-2, and 19% had a score of 3 or higher.

sworcester@frontlinemedcom.com

SOURCE: Broglie L et al. Abstract 16.

SALT LAKE CITY – Scores of 3 or higher on the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) are associated with an increased risk of posttransplant mortality in certain patients undergoing allogeneic HCT for nonmalignant disease, according to findings from a review of more than 4,000 patients.

The exception was in patients undergoing HCT for hemoglobinopathies, Larisa Broglie, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The findings of the study, which is the largest to date to validate the usefulness of the HCT-CI for risk assessment in HCT patients with nonmalignant disease, have important implications for patient counseling and decision making, said Dr. Broglie of the Medical College of Wisconsin, Milwaukee.

Of 4,083 children and adults who underwent a first allogeneic HCT for a nonmalignant disease between 2007 and 2014 and who had sufficient follow-up (median, 39 months), 61% had an HCT-CI score of 0, 20% had a score of 1-2, and 19% had a score of 3 or higher.

sworcester@frontlinemedcom.com

SOURCE: Broglie L et al. Abstract 16.

SALT LAKE CITY – Scores of 3 or higher on the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) are associated with an increased risk of posttransplant mortality in certain patients undergoing allogeneic HCT for nonmalignant disease, according to findings from a review of more than 4,000 patients.

The exception was in patients undergoing HCT for hemoglobinopathies, Larisa Broglie, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The findings of the study, which is the largest to date to validate the usefulness of the HCT-CI for risk assessment in HCT patients with nonmalignant disease, have important implications for patient counseling and decision making, said Dr. Broglie of the Medical College of Wisconsin, Milwaukee.

Of 4,083 children and adults who underwent a first allogeneic HCT for a nonmalignant disease between 2007 and 2014 and who had sufficient follow-up (median, 39 months), 61% had an HCT-CI score of 0, 20% had a score of 1-2, and 19% had a score of 3 or higher.

sworcester@frontlinemedcom.com

SOURCE: Broglie L et al. Abstract 16.

ATLANTA – GCLAM – the combined use of granulocyte colony-stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone – was well tolerated and had potent antileukemia activity in a phase 1/2 trial of adults with relapsed/refractory acute myeloid leukemia or high-grade myeloid neoplasms.

Of 40 patients who were treated with GCLAM (with mitoxantrone at the maximum tolerated dose of 16 mg/m² per day as established in phase 1 of the trial), 11 achieved a complete response (CR), and 13 achieved a complete response with incomplete blood count recovery (CRi), for an overall response rate of 60%, Anna B. Halpern, MD, reported at the annual meeting of the American Society of Hematology.

“Nine of the 11 CR patients and 11 of 13 with CRis were negative for minimal residual disease, for an overall MRD-negative CR rate of 23%,” said Dr. Halpern of the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.

Resistant disease occurred in 11 patients, she noted.

Median overall survival was 11.5 months, and the treatment-related mortality (TRM) rate was 5%.

Overall, 21 of 40 patients went to transplant, with a 49% 1-year survival rate, she said.

The patients had a median age of 63 years. Thirty-four had acute myeloid leukemia (AML), and 6 had high-grade myelodysplastic syndrome; 28 had secondary disease. Nineteen had primary refractory disease, 21 had relapsed disease after a median initial CR duration of 12 months, and 7 had prior allogeneic transplant. The median TRM score for all patients was 2.0, indicating a low risk for treatment-related mortality.

“Cytogenetics distribution, based on Medical Research Council criteria, was as expected,” she added.

At the mitoxantrone maximum tolerated dose of 16 mg/m² per day – which was established during phase 1 in 26 patients in whom higher dose levels (18 mg/m² per day) led to dose-limiting encephalopathy and cardiogenic shock – the most common grade 3 or greater adverse events included neutropenic fever, infectious complications, and hypoxia during therapy. This was largely attributed to volume overload and infection, Dr. Halpern said.

“Although three patients did have decreased ejection fraction in cycle 2, this was largely in the setting of sepsis, making the etiology difficult to ascribe to the anthracycline versus sepsis physiology,” she noted.

The median times to an absolute neutrophil count of 500/mcL or greater and platelet count of 50,000/mcL or greater were 29 days each, she noted.

A multivariable analysis controlling for baseline prognostic features showed that the mitoxantrone dose of 16 mg/m² per day was associated with significantly better overall survival, compared with a dose of 10 mg/m² per day used in a historical cohort according to standard GCLAM dosing (hazard ratio for death, 0.45). Additionally, more of those receiving a dose of 16 mg/m² per day went on to transplant (52% vs. 37%), she said. The overall response rate was also higher with the 16-mg/m² dose, but the difference was not statistically significant (odds ratio, 1.87).

“Further, the outcomes appear to be as good or better with GCLAM with mitoxantrone at 16 mg/m² compared to other salvage regimens used at our institution, including decitabine priming plus mitoxantrone, etoposide, and cytarabine [d/MEC] and G-CSF with clofarabine and high-dose cytarabine [GCLAC],” she said, noting that the examination is currently ongoing in a larger sample.

The initial analysis, however, showed that, after controlling for age, cytogenetic risk, first CR duration, and prior hematopoietic cell transplant, overall response and overall survival rates were better with GCLAM than with d/MEC (OR, 3.23; HR for death, 0.64) and that the overall response rate was similar between GCLAM and GCLAC (OR, 1.75), she said.

The findings are encouraging because outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission rates rarely exceeding 15%-20%, Dr. Halpern said.

The current study was undertaken based on promising results from a previous phase 2 study in poor-risk relapsed/refractory AML, which also showed encouraging activity with GCLAM and based on data suggesting benefit with escalated doses of anthracyclines in AML, she explained.

Patients 18 years and older were eligible if they had adequate organ function and a TRM score of 6.9 or lower, which corresponds to a predicted 28-day mortality of no more than 6.9% with standard induction chemotherapy. Those with uncontrolled infection or concomitant illness with expected survival of less than 1 year were excluded.

The phase 1 dose escalation involved cohorts of 6-12 patients who were assigned to receive mitoxantrone dose levels of 12, 14, 16, or 18 mg/m² per day on days 1-3. The doses of the remaining drugs in the combination were fixed at 300 mcg or 480 mcg of G-CSF on days 0-5, 5 mg/m² of cladribine on days 1-5, and 2 mg/m² of cytarabine on days 1-5.

“All patients received GCLAM induction at their assigned mitoxantrone dose level. If CR wasn’t achieved with cycle 1, a second identical course of GCLAM was given,” Dr. Halpern explained, noting that patients with resistant disease after 2 cycles were taken off the study.

If CR or CRi was achieved within 1-2 cycles of induction, up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed, and responders could proceed with transplant at any time.

In phase 2, patients received the maximum tolerated dose of mitoxantrone (16mg/m² per day), as defined in phase 1.

“Relapsed and refractory AML and high grade myeloid neoplasms are a challenging disease to treat. With an overall response rate of 60%, this regimen showed efficacy in a heavily pretreated patient population,” Dr. Halpern said. “And many of the responders were able to go on to receive a stem cell transplant, the only known curative option in this situation.”

A follow-up study is currently exploring the relative value of decitabine priming followed by GCLAM in this setting, she said.

Dr. Halpern reported having no relevant financial disclosures.

sworcester@frontlinemedcom.com

SOURCE: Halpern AB et al. ASH 2017, Abstract 149

ATLANTA – GCLAM – the combined use of granulocyte colony-stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone – was well tolerated and had potent antileukemia activity in a phase 1/2 trial of adults with relapsed/refractory acute myeloid leukemia or high-grade myeloid neoplasms.

Of 40 patients who were treated with GCLAM (with mitoxantrone at the maximum tolerated dose of 16 mg/m² per day as established in phase 1 of the trial), 11 achieved a complete response (CR), and 13 achieved a complete response with incomplete blood count recovery (CRi), for an overall response rate of 60%, Anna B. Halpern, MD, reported at the annual meeting of the American Society of Hematology.

“Nine of the 11 CR patients and 11 of 13 with CRis were negative for minimal residual disease, for an overall MRD-negative CR rate of 23%,” said Dr. Halpern of the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.

Resistant disease occurred in 11 patients, she noted.

Median overall survival was 11.5 months, and the treatment-related mortality (TRM) rate was 5%.

Overall, 21 of 40 patients went to transplant, with a 49% 1-year survival rate, she said.

The patients had a median age of 63 years. Thirty-four had acute myeloid leukemia (AML), and 6 had high-grade myelodysplastic syndrome; 28 had secondary disease. Nineteen had primary refractory disease, 21 had relapsed disease after a median initial CR duration of 12 months, and 7 had prior allogeneic transplant. The median TRM score for all patients was 2.0, indicating a low risk for treatment-related mortality.

“Cytogenetics distribution, based on Medical Research Council criteria, was as expected,” she added.

At the mitoxantrone maximum tolerated dose of 16 mg/m² per day – which was established during phase 1 in 26 patients in whom higher dose levels (18 mg/m² per day) led to dose-limiting encephalopathy and cardiogenic shock – the most common grade 3 or greater adverse events included neutropenic fever, infectious complications, and hypoxia during therapy. This was largely attributed to volume overload and infection, Dr. Halpern said.

“Although three patients did have decreased ejection fraction in cycle 2, this was largely in the setting of sepsis, making the etiology difficult to ascribe to the anthracycline versus sepsis physiology,” she noted.

The median times to an absolute neutrophil count of 500/mcL or greater and platelet count of 50,000/mcL or greater were 29 days each, she noted.

A multivariable analysis controlling for baseline prognostic features showed that the mitoxantrone dose of 16 mg/m² per day was associated with significantly better overall survival, compared with a dose of 10 mg/m² per day used in a historical cohort according to standard GCLAM dosing (hazard ratio for death, 0.45). Additionally, more of those receiving a dose of 16 mg/m² per day went on to transplant (52% vs. 37%), she said. The overall response rate was also higher with the 16-mg/m² dose, but the difference was not statistically significant (odds ratio, 1.87).

“Further, the outcomes appear to be as good or better with GCLAM with mitoxantrone at 16 mg/m² compared to other salvage regimens used at our institution, including decitabine priming plus mitoxantrone, etoposide, and cytarabine [d/MEC] and G-CSF with clofarabine and high-dose cytarabine [GCLAC],” she said, noting that the examination is currently ongoing in a larger sample.

The initial analysis, however, showed that, after controlling for age, cytogenetic risk, first CR duration, and prior hematopoietic cell transplant, overall response and overall survival rates were better with GCLAM than with d/MEC (OR, 3.23; HR for death, 0.64) and that the overall response rate was similar between GCLAM and GCLAC (OR, 1.75), she said.

The findings are encouraging because outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission rates rarely exceeding 15%-20%, Dr. Halpern said.

The current study was undertaken based on promising results from a previous phase 2 study in poor-risk relapsed/refractory AML, which also showed encouraging activity with GCLAM and based on data suggesting benefit with escalated doses of anthracyclines in AML, she explained.

Patients 18 years and older were eligible if they had adequate organ function and a TRM score of 6.9 or lower, which corresponds to a predicted 28-day mortality of no more than 6.9% with standard induction chemotherapy. Those with uncontrolled infection or concomitant illness with expected survival of less than 1 year were excluded.

The phase 1 dose escalation involved cohorts of 6-12 patients who were assigned to receive mitoxantrone dose levels of 12, 14, 16, or 18 mg/m² per day on days 1-3. The doses of the remaining drugs in the combination were fixed at 300 mcg or 480 mcg of G-CSF on days 0-5, 5 mg/m² of cladribine on days 1-5, and 2 mg/m² of cytarabine on days 1-5.

“All patients received GCLAM induction at their assigned mitoxantrone dose level. If CR wasn’t achieved with cycle 1, a second identical course of GCLAM was given,” Dr. Halpern explained, noting that patients with resistant disease after 2 cycles were taken off the study.

If CR or CRi was achieved within 1-2 cycles of induction, up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed, and responders could proceed with transplant at any time.

In phase 2, patients received the maximum tolerated dose of mitoxantrone (16mg/m² per day), as defined in phase 1.

“Relapsed and refractory AML and high grade myeloid neoplasms are a challenging disease to treat. With an overall response rate of 60%, this regimen showed efficacy in a heavily pretreated patient population,” Dr. Halpern said. “And many of the responders were able to go on to receive a stem cell transplant, the only known curative option in this situation.”

A follow-up study is currently exploring the relative value of decitabine priming followed by GCLAM in this setting, she said.

Dr. Halpern reported having no relevant financial disclosures.

sworcester@frontlinemedcom.com

SOURCE: Halpern AB et al. ASH 2017, Abstract 149

ATLANTA – GCLAM – the combined use of granulocyte colony-stimulating factor (G-CSF), cladribine, high-dose cytarabine, and mitoxantrone – was well tolerated and had potent antileukemia activity in a phase 1/2 trial of adults with relapsed/refractory acute myeloid leukemia or high-grade myeloid neoplasms.

Of 40 patients who were treated with GCLAM (with mitoxantrone at the maximum tolerated dose of 16 mg/m² per day as established in phase 1 of the trial), 11 achieved a complete response (CR), and 13 achieved a complete response with incomplete blood count recovery (CRi), for an overall response rate of 60%, Anna B. Halpern, MD, reported at the annual meeting of the American Society of Hematology.

“Nine of the 11 CR patients and 11 of 13 with CRis were negative for minimal residual disease, for an overall MRD-negative CR rate of 23%,” said Dr. Halpern of the University of Washington and the Fred Hutchinson Cancer Research Center, both in Seattle.

Resistant disease occurred in 11 patients, she noted.

Median overall survival was 11.5 months, and the treatment-related mortality (TRM) rate was 5%.

Overall, 21 of 40 patients went to transplant, with a 49% 1-year survival rate, she said.

The patients had a median age of 63 years. Thirty-four had acute myeloid leukemia (AML), and 6 had high-grade myelodysplastic syndrome; 28 had secondary disease. Nineteen had primary refractory disease, 21 had relapsed disease after a median initial CR duration of 12 months, and 7 had prior allogeneic transplant. The median TRM score for all patients was 2.0, indicating a low risk for treatment-related mortality.

“Cytogenetics distribution, based on Medical Research Council criteria, was as expected,” she added.

At the mitoxantrone maximum tolerated dose of 16 mg/m² per day – which was established during phase 1 in 26 patients in whom higher dose levels (18 mg/m² per day) led to dose-limiting encephalopathy and cardiogenic shock – the most common grade 3 or greater adverse events included neutropenic fever, infectious complications, and hypoxia during therapy. This was largely attributed to volume overload and infection, Dr. Halpern said.

“Although three patients did have decreased ejection fraction in cycle 2, this was largely in the setting of sepsis, making the etiology difficult to ascribe to the anthracycline versus sepsis physiology,” she noted.

The median times to an absolute neutrophil count of 500/mcL or greater and platelet count of 50,000/mcL or greater were 29 days each, she noted.

A multivariable analysis controlling for baseline prognostic features showed that the mitoxantrone dose of 16 mg/m² per day was associated with significantly better overall survival, compared with a dose of 10 mg/m² per day used in a historical cohort according to standard GCLAM dosing (hazard ratio for death, 0.45). Additionally, more of those receiving a dose of 16 mg/m² per day went on to transplant (52% vs. 37%), she said. The overall response rate was also higher with the 16-mg/m² dose, but the difference was not statistically significant (odds ratio, 1.87).

“Further, the outcomes appear to be as good or better with GCLAM with mitoxantrone at 16 mg/m² compared to other salvage regimens used at our institution, including decitabine priming plus mitoxantrone, etoposide, and cytarabine [d/MEC] and G-CSF with clofarabine and high-dose cytarabine [GCLAC],” she said, noting that the examination is currently ongoing in a larger sample.

The initial analysis, however, showed that, after controlling for age, cytogenetic risk, first CR duration, and prior hematopoietic cell transplant, overall response and overall survival rates were better with GCLAM than with d/MEC (OR, 3.23; HR for death, 0.64) and that the overall response rate was similar between GCLAM and GCLAC (OR, 1.75), she said.

The findings are encouraging because outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission rates rarely exceeding 15%-20%, Dr. Halpern said.

The current study was undertaken based on promising results from a previous phase 2 study in poor-risk relapsed/refractory AML, which also showed encouraging activity with GCLAM and based on data suggesting benefit with escalated doses of anthracyclines in AML, she explained.

Patients 18 years and older were eligible if they had adequate organ function and a TRM score of 6.9 or lower, which corresponds to a predicted 28-day mortality of no more than 6.9% with standard induction chemotherapy. Those with uncontrolled infection or concomitant illness with expected survival of less than 1 year were excluded.

The phase 1 dose escalation involved cohorts of 6-12 patients who were assigned to receive mitoxantrone dose levels of 12, 14, 16, or 18 mg/m² per day on days 1-3. The doses of the remaining drugs in the combination were fixed at 300 mcg or 480 mcg of G-CSF on days 0-5, 5 mg/m² of cladribine on days 1-5, and 2 mg/m² of cytarabine on days 1-5.

“All patients received GCLAM induction at their assigned mitoxantrone dose level. If CR wasn’t achieved with cycle 1, a second identical course of GCLAM was given,” Dr. Halpern explained, noting that patients with resistant disease after 2 cycles were taken off the study.

If CR or CRi was achieved within 1-2 cycles of induction, up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed, and responders could proceed with transplant at any time.

In phase 2, patients received the maximum tolerated dose of mitoxantrone (16mg/m² per day), as defined in phase 1.

“Relapsed and refractory AML and high grade myeloid neoplasms are a challenging disease to treat. With an overall response rate of 60%, this regimen showed efficacy in a heavily pretreated patient population,” Dr. Halpern said. “And many of the responders were able to go on to receive a stem cell transplant, the only known curative option in this situation.”

A follow-up study is currently exploring the relative value of decitabine priming followed by GCLAM in this setting, she said.

Dr. Halpern reported having no relevant financial disclosures.

sworcester@frontlinemedcom.com

SOURCE: Halpern AB et al. ASH 2017, Abstract 149

Thomas McIlraith, MD, SFHM, CLHM, never imagined he would be leading hospitalists and launching quality improvement (QI) initiatives, but only one year out of residency, he was doing just that.

In 2000, Dr. McIlraith had spent a year working as a hospitalist at South Sacramento (Calif.) Kaiser Permanente when he was tapped for the QI program director role.

“Obviously I didn’t have a lot of preparation,” he said of that first job as director. “All of a sudden I found myself in charge of 15 hospitalists, … and I really didn’t know what I was getting myself into.”

But a passion for quality improvement – for striving to always find ways to do better – put Dr. McIlraith on that path and kept him on it through two terms as chair of the hospital medicine department of Mercy Medical Group in Sacramento, where he was hired in 2004. He completed his second term in June 2016 (the department quintupled in size during his tenure), and then chose to return to the ranks as a hospitalist focusing on patient care – and on spending time with his kids before they finished high school.

sworcester@frontlinemedcom.com

Thomas McIlraith, MD, SFHM, CLHM, never imagined he would be leading hospitalists and launching quality improvement (QI) initiatives, but only one year out of residency, he was doing just that.

In 2000, Dr. McIlraith had spent a year working as a hospitalist at South Sacramento (Calif.) Kaiser Permanente when he was tapped for the QI program director role.

“Obviously I didn’t have a lot of preparation,” he said of that first job as director. “All of a sudden I found myself in charge of 15 hospitalists, … and I really didn’t know what I was getting myself into.”

But a passion for quality improvement – for striving to always find ways to do better – put Dr. McIlraith on that path and kept him on it through two terms as chair of the hospital medicine department of Mercy Medical Group in Sacramento, where he was hired in 2004. He completed his second term in June 2016 (the department quintupled in size during his tenure), and then chose to return to the ranks as a hospitalist focusing on patient care – and on spending time with his kids before they finished high school.

sworcester@frontlinemedcom.com

Thomas McIlraith, MD, SFHM, CLHM, never imagined he would be leading hospitalists and launching quality improvement (QI) initiatives, but only one year out of residency, he was doing just that.

In 2000, Dr. McIlraith had spent a year working as a hospitalist at South Sacramento (Calif.) Kaiser Permanente when he was tapped for the QI program director role.

“Obviously I didn’t have a lot of preparation,” he said of that first job as director. “All of a sudden I found myself in charge of 15 hospitalists, … and I really didn’t know what I was getting myself into.”

But a passion for quality improvement – for striving to always find ways to do better – put Dr. McIlraith on that path and kept him on it through two terms as chair of the hospital medicine department of Mercy Medical Group in Sacramento, where he was hired in 2004. He completed his second term in June 2016 (the department quintupled in size during his tenure), and then chose to return to the ranks as a hospitalist focusing on patient care – and on spending time with his kids before they finished high school.

sworcester@frontlinemedcom.com

SALT LAKE CITY, UTAH – An allogeneic off-the-shelf Epstein-Barr virus–targeted cytotoxic T lymphocyte–cell product known as ATA129 (tabelecleucel), is associated with a high response rate and a low rate of serious adverse events in patients with posttransplant lymphoproliferative disorder (PTLD), according to interim findings from an ongoing multicenter study.

The objective response rate at a median of 3.3 months among patients who were treated with ATA129 and who had sufficient follow-up to assess response was 80% in six patients treated following hematopoietic cell transplantation (HCT), and 83% in six who were treated after solid organ transplant (SOT), Susan E. Prockop, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Sharon Worcester/Frontline Medical News

Treatment-emergent adverse events occurred in 21 patients, including 17 who experienced grade 3 or greater adverse events or serious adverse events. Six were treatment related; one of those was grade 3 or greater, and five were considered serious adverse events. One patient had a grade 5 treatment-emergent adverse event (disease progression); two in the post-HCT group experienced graft-versus-host disease (GVHD), including one with grade 3 skin GVHD after sun exposure, which resolved with topical therapy; and one had grade 4 GVHD of the gastrointestinal tract and liver. One patient had a tumor flare that resolved, Dr. Prockop said.

“The most common safety events were GI disorders in seven patients, infections and infestations in five patients, and general disorders and administration site conditions in four,” she said. “No events have been categorized as drug reactions.”

PTLD, an EBV-driven lymphoproliferative disorder, is a life-threatening condition typically involving aggressive, clonal, diffuse large B cell lymphomas. Survival without therapy is a median of 31 days, she explained. Patients at high risk have a mortality rate of 72%, and these included those over age 30 years, those with GVHD at the time of diagnosis, and those with extranodal disease, three or more sites of disease involved, or central nervous system disease.

Although some patients respond to single-agent rituximab (Rituxan) therapy, those with rituximab-refractory disease have a median overall survival of 16-56 days, she said.

SOT recipients who develop indolent PTLD may respond to reduction of immunosuppression. Two-year risk-based survival in these patients is 88% with zero or one risk factors, and 0% with three or more risk factors, which include older age, poor performance status at diagnosis, high lactate dehydrogenase, CNS involvement, and short time from transplant to development of PTLD.

Rituximab monotherapy response rates are 76% in those with early lesions, and 47% in those with high-grade lesions, she said.

“Two-year overall survival in this patient population is 33%, reflecting their eligibility for multiagent chemotherapy, although this approach comes with significant morbidity,” she added, noting that patients failing rituximab experience increased chemotherapy-induced treatment-related mortality, compared with other lymphoma patients.

The benefit-risk profile observed in this multicenter trial is favorable with maximum response rates being reached after two cycles of therapy, and the findings confirm those from prior single-center studies, she said, noting that based on those earlier findings in patients treated with both primary and third-party donor EBV-cytotoxic T lymphocytes, the therapy is now an established National Comprehensive Cancer Network guideline therapeutic alternative for PTLD.

“Further evaluation in rituximab-refractory PTLD is ongoing in phase 3 registration trials,” she said.

Atara Biotherapeutics sponsored the trial. Dr. Prockop reported having no disclosures.

sworcester@frontlinemedcom.com

SOURCE: Prockop S et al. BMT Tandem Meetings Abstract 21.

SALT LAKE CITY, UTAH – An allogeneic off-the-shelf Epstein-Barr virus–targeted cytotoxic T lymphocyte–cell product known as ATA129 (tabelecleucel), is associated with a high response rate and a low rate of serious adverse events in patients with posttransplant lymphoproliferative disorder (PTLD), according to interim findings from an ongoing multicenter study.

The objective response rate at a median of 3.3 months among patients who were treated with ATA129 and who had sufficient follow-up to assess response was 80% in six patients treated following hematopoietic cell transplantation (HCT), and 83% in six who were treated after solid organ transplant (SOT), Susan E. Prockop, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Sharon Worcester/Frontline Medical News

Treatment-emergent adverse events occurred in 21 patients, including 17 who experienced grade 3 or greater adverse events or serious adverse events. Six were treatment related; one of those was grade 3 or greater, and five were considered serious adverse events. One patient had a grade 5 treatment-emergent adverse event (disease progression); two in the post-HCT group experienced graft-versus-host disease (GVHD), including one with grade 3 skin GVHD after sun exposure, which resolved with topical therapy; and one had grade 4 GVHD of the gastrointestinal tract and liver. One patient had a tumor flare that resolved, Dr. Prockop said.

“The most common safety events were GI disorders in seven patients, infections and infestations in five patients, and general disorders and administration site conditions in four,” she said. “No events have been categorized as drug reactions.”

PTLD, an EBV-driven lymphoproliferative disorder, is a life-threatening condition typically involving aggressive, clonal, diffuse large B cell lymphomas. Survival without therapy is a median of 31 days, she explained. Patients at high risk have a mortality rate of 72%, and these included those over age 30 years, those with GVHD at the time of diagnosis, and those with extranodal disease, three or more sites of disease involved, or central nervous system disease.

Although some patients respond to single-agent rituximab (Rituxan) therapy, those with rituximab-refractory disease have a median overall survival of 16-56 days, she said.

SOT recipients who develop indolent PTLD may respond to reduction of immunosuppression. Two-year risk-based survival in these patients is 88% with zero or one risk factors, and 0% with three or more risk factors, which include older age, poor performance status at diagnosis, high lactate dehydrogenase, CNS involvement, and short time from transplant to development of PTLD.

Rituximab monotherapy response rates are 76% in those with early lesions, and 47% in those with high-grade lesions, she said.

“Two-year overall survival in this patient population is 33%, reflecting their eligibility for multiagent chemotherapy, although this approach comes with significant morbidity,” she added, noting that patients failing rituximab experience increased chemotherapy-induced treatment-related mortality, compared with other lymphoma patients.

The benefit-risk profile observed in this multicenter trial is favorable with maximum response rates being reached after two cycles of therapy, and the findings confirm those from prior single-center studies, she said, noting that based on those earlier findings in patients treated with both primary and third-party donor EBV-cytotoxic T lymphocytes, the therapy is now an established National Comprehensive Cancer Network guideline therapeutic alternative for PTLD.

“Further evaluation in rituximab-refractory PTLD is ongoing in phase 3 registration trials,” she said.

Atara Biotherapeutics sponsored the trial. Dr. Prockop reported having no disclosures.

sworcester@frontlinemedcom.com

SOURCE: Prockop S et al. BMT Tandem Meetings Abstract 21.

SALT LAKE CITY, UTAH – An allogeneic off-the-shelf Epstein-Barr virus–targeted cytotoxic T lymphocyte–cell product known as ATA129 (tabelecleucel), is associated with a high response rate and a low rate of serious adverse events in patients with posttransplant lymphoproliferative disorder (PTLD), according to interim findings from an ongoing multicenter study.

The objective response rate at a median of 3.3 months among patients who were treated with ATA129 and who had sufficient follow-up to assess response was 80% in six patients treated following hematopoietic cell transplantation (HCT), and 83% in six who were treated after solid organ transplant (SOT), Susan E. Prockop, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

Sharon Worcester/Frontline Medical News

Treatment-emergent adverse events occurred in 21 patients, including 17 who experienced grade 3 or greater adverse events or serious adverse events. Six were treatment related; one of those was grade 3 or greater, and five were considered serious adverse events. One patient had a grade 5 treatment-emergent adverse event (disease progression); two in the post-HCT group experienced graft-versus-host disease (GVHD), including one with grade 3 skin GVHD after sun exposure, which resolved with topical therapy; and one had grade 4 GVHD of the gastrointestinal tract and liver. One patient had a tumor flare that resolved, Dr. Prockop said.

“The most common safety events were GI disorders in seven patients, infections and infestations in five patients, and general disorders and administration site conditions in four,” she said. “No events have been categorized as drug reactions.”

PTLD, an EBV-driven lymphoproliferative disorder, is a life-threatening condition typically involving aggressive, clonal, diffuse large B cell lymphomas. Survival without therapy is a median of 31 days, she explained. Patients at high risk have a mortality rate of 72%, and these included those over age 30 years, those with GVHD at the time of diagnosis, and those with extranodal disease, three or more sites of disease involved, or central nervous system disease.

Although some patients respond to single-agent rituximab (Rituxan) therapy, those with rituximab-refractory disease have a median overall survival of 16-56 days, she said.

SOT recipients who develop indolent PTLD may respond to reduction of immunosuppression. Two-year risk-based survival in these patients is 88% with zero or one risk factors, and 0% with three or more risk factors, which include older age, poor performance status at diagnosis, high lactate dehydrogenase, CNS involvement, and short time from transplant to development of PTLD.

Rituximab monotherapy response rates are 76% in those with early lesions, and 47% in those with high-grade lesions, she said.

“Two-year overall survival in this patient population is 33%, reflecting their eligibility for multiagent chemotherapy, although this approach comes with significant morbidity,” she added, noting that patients failing rituximab experience increased chemotherapy-induced treatment-related mortality, compared with other lymphoma patients.

The benefit-risk profile observed in this multicenter trial is favorable with maximum response rates being reached after two cycles of therapy, and the findings confirm those from prior single-center studies, she said, noting that based on those earlier findings in patients treated with both primary and third-party donor EBV-cytotoxic T lymphocytes, the therapy is now an established National Comprehensive Cancer Network guideline therapeutic alternative for PTLD.

“Further evaluation in rituximab-refractory PTLD is ongoing in phase 3 registration trials,” she said.

Atara Biotherapeutics sponsored the trial. Dr. Prockop reported having no disclosures.

sworcester@frontlinemedcom.com

SOURCE: Prockop S et al. BMT Tandem Meetings Abstract 21.

SALT LAKE CITY – The use of Janus kinase (JAK) inhibitor therapy prior to hematopoietic stem cell transplantation is safe and may improve posttransplant survival in patients with myelofibrosis, according to findings from an ongoing prospective phase 2 study.

The 1-year overall survival rate among the 28 initial patients in the single-center study of JAK inhibitor therapy followed by myeloablative or reduced-intensity hematopoietic cell transplantation (HCT) was 93%. The 2-year survival rate was 89%, compared with 54% in a closely matched historical cohort of intermediate-2–risk patients who did not receive pre-HCT JAK inhibitor therapy, Rachel B. Salit, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

sworcester@frontlinemedcom.com

SOURCE: Salit R et al. BMT Tandem Meetings, Abstract 17.

SALT LAKE CITY – The use of Janus kinase (JAK) inhibitor therapy prior to hematopoietic stem cell transplantation is safe and may improve posttransplant survival in patients with myelofibrosis, according to findings from an ongoing prospective phase 2 study.

The 1-year overall survival rate among the 28 initial patients in the single-center study of JAK inhibitor therapy followed by myeloablative or reduced-intensity hematopoietic cell transplantation (HCT) was 93%. The 2-year survival rate was 89%, compared with 54% in a closely matched historical cohort of intermediate-2–risk patients who did not receive pre-HCT JAK inhibitor therapy, Rachel B. Salit, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

sworcester@frontlinemedcom.com

SOURCE: Salit R et al. BMT Tandem Meetings, Abstract 17.

SALT LAKE CITY – The use of Janus kinase (JAK) inhibitor therapy prior to hematopoietic stem cell transplantation is safe and may improve posttransplant survival in patients with myelofibrosis, according to findings from an ongoing prospective phase 2 study.

The 1-year overall survival rate among the 28 initial patients in the single-center study of JAK inhibitor therapy followed by myeloablative or reduced-intensity hematopoietic cell transplantation (HCT) was 93%. The 2-year survival rate was 89%, compared with 54% in a closely matched historical cohort of intermediate-2–risk patients who did not receive pre-HCT JAK inhibitor therapy, Rachel B. Salit, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

sworcester@frontlinemedcom.com

SOURCE: Salit R et al. BMT Tandem Meetings, Abstract 17.

ATLANTA – Maintenance therapy with the synthetic retinoid tamibarotene is more effective than all-trans retinoic acid (ATRA), for decreasing the relapse rate in patients with acute promyelocytic leukemia (APL) – a subtype of acute myeloid leukemia, according to 7-year findings from the JALSG-APL204 randomized controlled trial.

The relapse-free survival findings were particularly pronounced among high-risk patients with leukocyte counts of at least 10,000 per microliter, Akihiro Takeshita, MD, PhD, reported at the annual meeting of the American Society of Hematology.

“These results could lead to a new strategy for the treatment of high-risk patients, which is one of the recent priority issues in the treatment of APL,” said Dr. Takeshita of Hamamatsu (Japan) University.

Of 344 eligible patients aged 15-70 years with newly diagnosed APL and documented cytogenetic and/or molecular evidence of chromosomal translocation t(15;17) or PML/RAR-alpha gene expression, 269 entered the maintenance phase of the study after completing three courses of consolidation therapy and were assigned to receive ATRA or tamibarotene. At a mean follow-up of 7 years, the relapse-free survival rate was 84% in the 135 patients in the ATRA arm, compared with 93% among the 134 patients in the tamibarotene arm.

The difference between the groups was statistically significant, but an even greater difference was seen when the analysis was restricted to 52 high-risk patients with an initial leukocyte count of at least 10,000 per microliter (62% vs. 89%).

Both treatments were generally well tolerated, Dr. Takeshita reported.

Study subjects received ATRA at a daily dose of 45 mg/m² for remission induction. Once complete remission was achieved, they received chemotherapy based on their initial leukocyte and blast count in the peripheral blood. Those who achieved molecular remission after consolidation chemotherapy were included in the current maintenance phase of the study. During this phase, ATRA was given at a daily dose of 45 mg/m² divided into 3 doses for 14 days, and tamibarotene was given at a daily dose of 6 mg/m² divided into 2 doses for 14 days. Each cycle of treatment was repeated every 3 months for 2 years.

Adverse events included secondary hematopoietic disorders in 12 cases, malignancies in 9 cases, and late cardiac complications of grade 3 or higher in 5 cases, but no significant difference in the rates of these events was seen between the two treatment groups, Dr. Takeshita noted.

Tamibarotene was studied in this trial because, compared with ATRA, it has been shown to have about a 10-fold increase in potency for inducing in vitro differentiation of NB-4 cells, enhanced chemical stability, and low affinity for cellular RA-binding protein.

“The clinical efficacy of tamibarotene for the treatment of APL has also been reported,” Dr. Takeshita added.

In the initial phases of the trial, no difference was seen between ATRA and tamibarotene with respect to 4-year relapse-free survival, but there did appear to be improved efficacy with tamibarotene in high-risk patients, which warranted further investigation, he said.

The current findings demonstrate the efficacy of tamibarotene vs. ATRA for decreasing the relapse rate at the 7-year observation point, and confirm the benefit in high-risk patients that was seen in earlier analyses, he concluded.

Dr. Takeshita reported receiving research funding from Chugai Pharmaceutical, Astellas Pharma, Pfizer Japan, and Takeda Pharmaceutical.

sworcester@frontlinemedcom.com

SOURCE: Takeshita A et al., ASH 2017, abstract 642.

ATLANTA – Maintenance therapy with the synthetic retinoid tamibarotene is more effective than all-trans retinoic acid (ATRA), for decreasing the relapse rate in patients with acute promyelocytic leukemia (APL) – a subtype of acute myeloid leukemia, according to 7-year findings from the JALSG-APL204 randomized controlled trial.

The relapse-free survival findings were particularly pronounced among high-risk patients with leukocyte counts of at least 10,000 per microliter, Akihiro Takeshita, MD, PhD, reported at the annual meeting of the American Society of Hematology.

“These results could lead to a new strategy for the treatment of high-risk patients, which is one of the recent priority issues in the treatment of APL,” said Dr. Takeshita of Hamamatsu (Japan) University.

Of 344 eligible patients aged 15-70 years with newly diagnosed APL and documented cytogenetic and/or molecular evidence of chromosomal translocation t(15;17) or PML/RAR-alpha gene expression, 269 entered the maintenance phase of the study after completing three courses of consolidation therapy and were assigned to receive ATRA or tamibarotene. At a mean follow-up of 7 years, the relapse-free survival rate was 84% in the 135 patients in the ATRA arm, compared with 93% among the 134 patients in the tamibarotene arm.

The difference between the groups was statistically significant, but an even greater difference was seen when the analysis was restricted to 52 high-risk patients with an initial leukocyte count of at least 10,000 per microliter (62% vs. 89%).

Both treatments were generally well tolerated, Dr. Takeshita reported.

Study subjects received ATRA at a daily dose of 45 mg/m² for remission induction. Once complete remission was achieved, they received chemotherapy based on their initial leukocyte and blast count in the peripheral blood. Those who achieved molecular remission after consolidation chemotherapy were included in the current maintenance phase of the study. During this phase, ATRA was given at a daily dose of 45 mg/m² divided into 3 doses for 14 days, and tamibarotene was given at a daily dose of 6 mg/m² divided into 2 doses for 14 days. Each cycle of treatment was repeated every 3 months for 2 years.

Adverse events included secondary hematopoietic disorders in 12 cases, malignancies in 9 cases, and late cardiac complications of grade 3 or higher in 5 cases, but no significant difference in the rates of these events was seen between the two treatment groups, Dr. Takeshita noted.

Tamibarotene was studied in this trial because, compared with ATRA, it has been shown to have about a 10-fold increase in potency for inducing in vitro differentiation of NB-4 cells, enhanced chemical stability, and low affinity for cellular RA-binding protein.

“The clinical efficacy of tamibarotene for the treatment of APL has also been reported,” Dr. Takeshita added.

In the initial phases of the trial, no difference was seen between ATRA and tamibarotene with respect to 4-year relapse-free survival, but there did appear to be improved efficacy with tamibarotene in high-risk patients, which warranted further investigation, he said.

The current findings demonstrate the efficacy of tamibarotene vs. ATRA for decreasing the relapse rate at the 7-year observation point, and confirm the benefit in high-risk patients that was seen in earlier analyses, he concluded.

Dr. Takeshita reported receiving research funding from Chugai Pharmaceutical, Astellas Pharma, Pfizer Japan, and Takeda Pharmaceutical.

sworcester@frontlinemedcom.com

SOURCE: Takeshita A et al., ASH 2017, abstract 642.

ATLANTA – Maintenance therapy with the synthetic retinoid tamibarotene is more effective than all-trans retinoic acid (ATRA), for decreasing the relapse rate in patients with acute promyelocytic leukemia (APL) – a subtype of acute myeloid leukemia, according to 7-year findings from the JALSG-APL204 randomized controlled trial.

The relapse-free survival findings were particularly pronounced among high-risk patients with leukocyte counts of at least 10,000 per microliter, Akihiro Takeshita, MD, PhD, reported at the annual meeting of the American Society of Hematology.

“These results could lead to a new strategy for the treatment of high-risk patients, which is one of the recent priority issues in the treatment of APL,” said Dr. Takeshita of Hamamatsu (Japan) University.

Of 344 eligible patients aged 15-70 years with newly diagnosed APL and documented cytogenetic and/or molecular evidence of chromosomal translocation t(15;17) or PML/RAR-alpha gene expression, 269 entered the maintenance phase of the study after completing three courses of consolidation therapy and were assigned to receive ATRA or tamibarotene. At a mean follow-up of 7 years, the relapse-free survival rate was 84% in the 135 patients in the ATRA arm, compared with 93% among the 134 patients in the tamibarotene arm.

The difference between the groups was statistically significant, but an even greater difference was seen when the analysis was restricted to 52 high-risk patients with an initial leukocyte count of at least 10,000 per microliter (62% vs. 89%).

Both treatments were generally well tolerated, Dr. Takeshita reported.

Study subjects received ATRA at a daily dose of 45 mg/m² for remission induction. Once complete remission was achieved, they received chemotherapy based on their initial leukocyte and blast count in the peripheral blood. Those who achieved molecular remission after consolidation chemotherapy were included in the current maintenance phase of the study. During this phase, ATRA was given at a daily dose of 45 mg/m² divided into 3 doses for 14 days, and tamibarotene was given at a daily dose of 6 mg/m² divided into 2 doses for 14 days. Each cycle of treatment was repeated every 3 months for 2 years.

Adverse events included secondary hematopoietic disorders in 12 cases, malignancies in 9 cases, and late cardiac complications of grade 3 or higher in 5 cases, but no significant difference in the rates of these events was seen between the two treatment groups, Dr. Takeshita noted.

Tamibarotene was studied in this trial because, compared with ATRA, it has been shown to have about a 10-fold increase in potency for inducing in vitro differentiation of NB-4 cells, enhanced chemical stability, and low affinity for cellular RA-binding protein.

“The clinical efficacy of tamibarotene for the treatment of APL has also been reported,” Dr. Takeshita added.

In the initial phases of the trial, no difference was seen between ATRA and tamibarotene with respect to 4-year relapse-free survival, but there did appear to be improved efficacy with tamibarotene in high-risk patients, which warranted further investigation, he said.

The current findings demonstrate the efficacy of tamibarotene vs. ATRA for decreasing the relapse rate at the 7-year observation point, and confirm the benefit in high-risk patients that was seen in earlier analyses, he concluded.

Dr. Takeshita reported receiving research funding from Chugai Pharmaceutical, Astellas Pharma, Pfizer Japan, and Takeda Pharmaceutical.

sworcester@frontlinemedcom.com

SOURCE: Takeshita A et al., ASH 2017, abstract 642.

Adding metronomic oral cyclophosphamide to trastuzumab and pertuzumab in frail elderly women with human epidermal growth factor receptor 2–positive metastatic breast cancer improved median progression-free survival by 7 months – with acceptable toxicity – vs. dual HER2 blockade alone in a randomized, open-label, phase 2 trial.

After a median follow-up of 20.7 months, the median progression-free survival (PFS) among 41 women who received trastuzumab and pertuzumab plus metronomic oral cyclophosphamide was 12.7 months, compared with 5.6 months among 39 women who received only trastuzumab and pertuzumab. Estimated PFS at 6 months was 73.4% and 46.2% in the groups, respectively (hazard ratio, 0.65), Hans Wildiers, MD, PhD, of University Hospitals Leuven, Belgium, and his colleagues reported in Lancet Oncology.

The most frequent grade 3-4 adverse events occurring in each group, respectively, were hypertension (12% and 15%), diarrhea (12% and 10%), dyspnea (10% and 5%), fatigue (5% and 8%), and pain (5% in each group). Thromboembolic events occurred in four patients (10%) receiving cyclophosphamide, while none occurred in the dual HER2 blockade-only group. Severe cardiac toxicities were occasionally observed in both groups.

Study subjects were women aged at least 70 years, or at least 60 years with confirmed functional restrictions. All had confirmed HER2-positive metastatic breast cancer and no prior chemotherapy for metastatic disease. They received either intravenous trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks, and intravenous pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks (median of 6 cycles), or those same doses of trastuzumab and pertuzumab plus metronomic oral cyclophosphamide at a dose of 50 mg daily (median of 13 cycles). Subsequent treatment with trastuzumab emtansine in 29 patients who progressed during the study was active and well tolerated; the overall PFS at 6 months in this group of patients was 49.5% and median PFS was 5 months after starting trastuzumab emtansine.

“The results of this study indicate that the benefit of avoiding the side effects of chemotherapy with the use of dual anti–HER2 blockade only does not compensate for an important loss of activity in the metastatic setting,” the investigators wrote, concluding that “trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, potentially followed by trastuzumab emtansine after progression, might delay the need for, or supersede, the use of taxane-based chemotherapy in this population.”

Further evaluation of this combination in a randomized phase 3 study is warranted, as the phase 2 findings do not provide “robust justification for a change in practice.” They do, however, provide a scientific framework for supporting more specific trials in older patients, who compromise nearly a third of breast cancer patients worldwide, and up to 50% in high-income countries, they said.

This study was funded by F Hoffmann-La Roche. Dr. Wildiers has received research grants from Roche, and personal fees to his institute from Roche, Amgen, Novartis, Pfizer, Puma, and Celldex. Other authors also reported receiving research or other support from Roche Products, Eisai, Novartis Pharmaceuticals UK, Astellas/Medivation, Astra Zeneca, Celgene, Daiichi-Sankyo, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck Sharp & Dohme, Merus BV, Mylan, Novartis, Pfizer, Pierre Fabre, Sanofi, and Teva.

sworcester@frontlinemedcom.com

SOURCE: Wildiers H et al. Lancet Oncol. 2018 Feb 9. doi: 10.1016/S1470-2045(18)30083-4.

Adding metronomic oral cyclophosphamide to trastuzumab and pertuzumab in frail elderly women with human epidermal growth factor receptor 2–positive metastatic breast cancer improved median progression-free survival by 7 months – with acceptable toxicity – vs. dual HER2 blockade alone in a randomized, open-label, phase 2 trial.

After a median follow-up of 20.7 months, the median progression-free survival (PFS) among 41 women who received trastuzumab and pertuzumab plus metronomic oral cyclophosphamide was 12.7 months, compared with 5.6 months among 39 women who received only trastuzumab and pertuzumab. Estimated PFS at 6 months was 73.4% and 46.2% in the groups, respectively (hazard ratio, 0.65), Hans Wildiers, MD, PhD, of University Hospitals Leuven, Belgium, and his colleagues reported in Lancet Oncology.

The most frequent grade 3-4 adverse events occurring in each group, respectively, were hypertension (12% and 15%), diarrhea (12% and 10%), dyspnea (10% and 5%), fatigue (5% and 8%), and pain (5% in each group). Thromboembolic events occurred in four patients (10%) receiving cyclophosphamide, while none occurred in the dual HER2 blockade-only group. Severe cardiac toxicities were occasionally observed in both groups.

Study subjects were women aged at least 70 years, or at least 60 years with confirmed functional restrictions. All had confirmed HER2-positive metastatic breast cancer and no prior chemotherapy for metastatic disease. They received either intravenous trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks, and intravenous pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks (median of 6 cycles), or those same doses of trastuzumab and pertuzumab plus metronomic oral cyclophosphamide at a dose of 50 mg daily (median of 13 cycles). Subsequent treatment with trastuzumab emtansine in 29 patients who progressed during the study was active and well tolerated; the overall PFS at 6 months in this group of patients was 49.5% and median PFS was 5 months after starting trastuzumab emtansine.

“The results of this study indicate that the benefit of avoiding the side effects of chemotherapy with the use of dual anti–HER2 blockade only does not compensate for an important loss of activity in the metastatic setting,” the investigators wrote, concluding that “trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, potentially followed by trastuzumab emtansine after progression, might delay the need for, or supersede, the use of taxane-based chemotherapy in this population.”

Further evaluation of this combination in a randomized phase 3 study is warranted, as the phase 2 findings do not provide “robust justification for a change in practice.” They do, however, provide a scientific framework for supporting more specific trials in older patients, who compromise nearly a third of breast cancer patients worldwide, and up to 50% in high-income countries, they said.

This study was funded by F Hoffmann-La Roche. Dr. Wildiers has received research grants from Roche, and personal fees to his institute from Roche, Amgen, Novartis, Pfizer, Puma, and Celldex. Other authors also reported receiving research or other support from Roche Products, Eisai, Novartis Pharmaceuticals UK, Astellas/Medivation, Astra Zeneca, Celgene, Daiichi-Sankyo, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck Sharp & Dohme, Merus BV, Mylan, Novartis, Pfizer, Pierre Fabre, Sanofi, and Teva.

sworcester@frontlinemedcom.com

SOURCE: Wildiers H et al. Lancet Oncol. 2018 Feb 9. doi: 10.1016/S1470-2045(18)30083-4.

Adding metronomic oral cyclophosphamide to trastuzumab and pertuzumab in frail elderly women with human epidermal growth factor receptor 2–positive metastatic breast cancer improved median progression-free survival by 7 months – with acceptable toxicity – vs. dual HER2 blockade alone in a randomized, open-label, phase 2 trial.

After a median follow-up of 20.7 months, the median progression-free survival (PFS) among 41 women who received trastuzumab and pertuzumab plus metronomic oral cyclophosphamide was 12.7 months, compared with 5.6 months among 39 women who received only trastuzumab and pertuzumab. Estimated PFS at 6 months was 73.4% and 46.2% in the groups, respectively (hazard ratio, 0.65), Hans Wildiers, MD, PhD, of University Hospitals Leuven, Belgium, and his colleagues reported in Lancet Oncology.

The most frequent grade 3-4 adverse events occurring in each group, respectively, were hypertension (12% and 15%), diarrhea (12% and 10%), dyspnea (10% and 5%), fatigue (5% and 8%), and pain (5% in each group). Thromboembolic events occurred in four patients (10%) receiving cyclophosphamide, while none occurred in the dual HER2 blockade-only group. Severe cardiac toxicities were occasionally observed in both groups.

Study subjects were women aged at least 70 years, or at least 60 years with confirmed functional restrictions. All had confirmed HER2-positive metastatic breast cancer and no prior chemotherapy for metastatic disease. They received either intravenous trastuzumab at a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks, and intravenous pertuzumab at a loading dose of 840 mg followed by 420 mg every 3 weeks (median of 6 cycles), or those same doses of trastuzumab and pertuzumab plus metronomic oral cyclophosphamide at a dose of 50 mg daily (median of 13 cycles). Subsequent treatment with trastuzumab emtansine in 29 patients who progressed during the study was active and well tolerated; the overall PFS at 6 months in this group of patients was 49.5% and median PFS was 5 months after starting trastuzumab emtansine.

“The results of this study indicate that the benefit of avoiding the side effects of chemotherapy with the use of dual anti–HER2 blockade only does not compensate for an important loss of activity in the metastatic setting,” the investigators wrote, concluding that “trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, potentially followed by trastuzumab emtansine after progression, might delay the need for, or supersede, the use of taxane-based chemotherapy in this population.”

Further evaluation of this combination in a randomized phase 3 study is warranted, as the phase 2 findings do not provide “robust justification for a change in practice.” They do, however, provide a scientific framework for supporting more specific trials in older patients, who compromise nearly a third of breast cancer patients worldwide, and up to 50% in high-income countries, they said.

This study was funded by F Hoffmann-La Roche. Dr. Wildiers has received research grants from Roche, and personal fees to his institute from Roche, Amgen, Novartis, Pfizer, Puma, and Celldex. Other authors also reported receiving research or other support from Roche Products, Eisai, Novartis Pharmaceuticals UK, Astellas/Medivation, Astra Zeneca, Celgene, Daiichi-Sankyo, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Merck Sharp & Dohme, Merus BV, Mylan, Novartis, Pfizer, Pierre Fabre, Sanofi, and Teva.

sworcester@frontlinemedcom.com

SOURCE: Wildiers H et al. Lancet Oncol. 2018 Feb 9. doi: 10.1016/S1470-2045(18)30083-4.

SAN FRANCISCO – An analysis of the T-cell repertoire in nearly 400 patients with stage I-III non–small cell lung cancer (NSCLC) suggests that patients with a more tumor-focused repertoire have better outcomes.

The findings, which suggest that patients with fewer T cells and with lower clonality in tumor-adjacent normal lung tissue fare better, could have implications for the use of tumor-infiltrating lymphocyte (TIL) therapy and checkpoint blockade – and possibly other therapies – in these patients, according to Alexandre Reuben, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

Studying the T-cell repertoire in the lung can be rather “messy,” because many T cells may be responding to the outside environment, but comparing findings in the normal lung with those in tumor tissue helps to clarify things, Dr. Reuben said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

Why study the T-cell repertoire?

The successes seen with immune checkpoint blockade in recent years are largely a result of the ability of these therapies to enhance the antitumor T-cell response. Interestingly, checkpoint blockade works better in tumor types like lung cancer that have a high mutational load, Dr. Reuben said, explaining that this is largely attributable to the ability of the mutations to increase tumor immunogenicity through generation of tumor-specific antigens, which can then be targeted by the T-cell response.

This relationship between the mutational and neoantigen burden and patient outcomes has been described, but the role of the T-cell repertoire and how it relates to patient outcomes is less clear.

Hypothesizing that T-cell repertoire would be associated with survival in patients with NSCLC, he and his colleagues collected peripheral blood, normal lung, and tumor tissue, and performed T cell–receptor sequencing, among other analyses, in 398 patients.

“T cells recognize antigens through their T-cell receptor, as a result of which they undergo clonal expansion. Therefore, by sequencing the variable region of the T-cell receptor, one can gain insight into the T cells that are responding within the sample, as well as the overall T-cell repertoire,” he explained.

This provides information on T-cell density and richness, and thus on the diversity of the T-cell repertoire, he said, adding that it is possible to go beyond that and plot T cells based on their frequency in a sample to study clonality.

Since these T cells tend to expand clonally as a result of activation, uneven distribution would be associated with a reactive T-cell repertoire, as described by a high T-cell clonality.

An assessment to determine how the T-cell repertoire relates to clinical characteristics and response revealed a few interesting correlations. For example, adenocarcinomas tended to be more densely infiltrated than squamous cell carcinomas, smaller tumors were also more densely infiltrated by T cells than were their larger counterparts, and in smokers the T-cell repertoire appeared much more reactive than in nonsmokers.

“But ultimately, we didn’t see the [direct correlations between the T-cell repertoire and outcomes] we were hoping to see,” Dr. Reuben said, noting that this could be because of environmental influences.

“Obviously the lung is exposed to the outside environment, which could be masking some of the antitumor T-cell responses we were hoping to study,” he explained. “So we used a more holistic approach, integrating the peripheral blood and normal lung with tumor repertoire going forward.”
 

T cells in normal lung vs. tumor

Measuring the proportion of the T-cell repertoire that is shared in peripheral blood vs. normal lung and vs. tumor tissue showed that there is very little in common between them.

“However, when you compare the normal lung to the tumor, there’s much more homology in the T-cell repertoire,” he said, noting that, given the T-cell expansion resulting from antigenic stimulation, focusing on the most dominant cells in a sample highlights those most likely to be responding to antigens. “When we did that ... we saw even more of an enrichment in the homology between the normal lung and tumor T-cell repertoire, suggesting certain parallels in the ongoing immune responses across both these compartments.”

Further, T-cell density and diversity were actually higher in the tumor than in the normal lung in about two-thirds of patients, he said.

“However, surprisingly ... clonality appears to be much higher in the normal lung than in the tumor,” he added, noting that this was the case in about 75% of patients.

These findings raise three key questions:
 

Why is clonality higher in the normal lung?

T cells are not confined to a specific part of the host and are free to circulate, Dr. Reuben said.

“However, the closer you get to a site of inflammation, the higher the enrichment for T cells that are relevant to that specific site of inflammation, so you can use these statistical methods to enrich for T cells that are more relevant and try to subtract out T cells that are simply circulating through the organ,” he noted.

He and his colleagues used these methods and compared both normal lung and tumor to the peripheral blood, focusing only on clones that were statistically enriched in these two compartments “to really eliminate a lot of the background that may have been caused by the low-frequency T cells in these samples.”

When you look at the lung enriched T-cell repertoire between normal lung vs. tumor, the homology increases quite significantly, suggesting that by subtracting these T cells that are circulating through the host and not likely relevant to the antigenic response, you’re increasing the homology and further highlighting some of the aforementioned parallels in the ongoing immune responses between both sites, he said.

“Now if you look at clonality, there’s really no clear trend ... in the total T-cell repertoire or the enriched repertoire focusing on the normal lung, but if you look at the tumor, there’s a trend toward increased clonality in all patients – to the extent where you no longer see a difference in clonality between the normal lung and tumor, suggesting that this enrichment is allowing us to focus increasingly on T cells relevant to the antitumor response,” he added.

T-cell clonality is highly reliant on the ability of T cells to expand as a result of antigenic stimulation, and immune profiling showed that programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) were higher within the tumor, suggesting that there is some dysfunction on both sides of this interaction, which could also explain the lower clonality originally seen within the tumor, he said.
 

Why is the T-cell repertoire so similar across normal lung and tumor (and what are these T cells really recognizing)?

“Well, we performed whole-exome sequencing and it’s really no surprise that mutational load is substantial in the tumor, but what was surprising was the amount of mutations we detected in the normal lung,” Dr. Reuben said.

The number was lower than in the tumor, though still considerable, and included a large proportion that were shared mutations between the normal lung and the tumor, he noted.

A closer look at the shared mutations showed that they correlated positively with the proportion of shared dominant T cells between the normal lung and the tumor, suggesting that some of the shared T cells may be targeting shared mutations between the normal lung and the tumor. The correlation was weak, but statistically significant, so while it doesn’t account for all of the overlap, it likely accounts for some of the homology, he said.

In a paper published last year, Mark M Davis, PhD, of Stanford (Calif.) University and his colleagues went beyond standard analysis of the T-cell repertoire and identified residues specific to certain antigens in order to classify T cells based on their likely reactivity. Dr. Reuben and his colleagues collaborated with that group to determine whether T cells were predominantly viral or nonviral.

“If you focus on the normal lung and tumor, you don’t see much of a trend. In some patients there are more viral motifs, and in others are more nonviral motifs, but what was striking was the enrichment for viral motifs that we saw when we focused on the T cells that were shared between the normal lung and tumor,” Dr Reuben said.

In fact, 88% of patients had more viral motifs within their shared T cells vs. only 33% in the normal lung and 30% in tumor.

“So T cells that are shared may be recognizing a combination of shared mutations and/or viruses,” he explained.
 

How does the T-cell repertoire relate to outcomes?

A focus on the normal lung showed that patients with fewer T cells and lower clonality had better outcomes.

“What does this mean? It suggests that potentially, in these patients, the immune response in the lung is less distracted by outside pathogens and agents unrelated to the tumor, potentially providing the opportunity for a more focused antitumor T-cell response,” Dr. Reuben said, concluding that “T-cell density is higher, but clonality is lower in tumor vs. normal lung, there’s a substantial overlap in the T-cell repertoire between the normal lung and the tumor (including many T cells which may be reactive to shared mutations and/or viruses), and it seems like a more tumor-focused T-cell repertoire in the lung may be associated with improved outcomes.”

In an interview, Dr. Reuben said the findings have certain therapeutic implications, because most current therapies target the T-cell response whether by design or consequence.

“Considering the large proportion of T cells found in lung tumors which are unrelated to tumor responses, expansion of the wrong T cells – whether these target viruses or shared mutations between the normal lung and tumor – could potentially offer no benefit to the patient, because it would likely not contribute to eradicating their tumor,” he explained. “Furthermore, targeting T cells (through checkpoint blockade or TIL therapy) that are reactive to shared mutations could increase the potential for toxicity within these patients. Therefore, a better understanding of the T-cell repertoire in the lung is necessary to increase the specificity and success rates of current immunotherapies.”

Invited discussant, Antoni Ribas, MD, of the University of California, Los Angeles, suggested that the finding of a substantial number of shared T-cells is likely a baseline phenomenon, and that on-therapy biopsies in patients who respond to treatment would better separate and expand the T cells that responded from those that did not.

In fact, Dr. Reuben and his colleagues have expanded their research in this manner.

“We are now studying this phenomenon longitudinally in patients receiving checkpoint blockade to see how these factors evolve over the course of therapy,” he said.

Dr. Reuben reported having no disclosures. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or advisor for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.

sworcester@frontlinemedcom.com

SOURCE: Reuben A et al. Clinical Immuno-Oncology Symposium Abstract 140.

SAN FRANCISCO – An analysis of the T-cell repertoire in nearly 400 patients with stage I-III non–small cell lung cancer (NSCLC) suggests that patients with a more tumor-focused repertoire have better outcomes.

The findings, which suggest that patients with fewer T cells and with lower clonality in tumor-adjacent normal lung tissue fare better, could have implications for the use of tumor-infiltrating lymphocyte (TIL) therapy and checkpoint blockade – and possibly other therapies – in these patients, according to Alexandre Reuben, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

Studying the T-cell repertoire in the lung can be rather “messy,” because many T cells may be responding to the outside environment, but comparing findings in the normal lung with those in tumor tissue helps to clarify things, Dr. Reuben said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

Why study the T-cell repertoire?

The successes seen with immune checkpoint blockade in recent years are largely a result of the ability of these therapies to enhance the antitumor T-cell response. Interestingly, checkpoint blockade works better in tumor types like lung cancer that have a high mutational load, Dr. Reuben said, explaining that this is largely attributable to the ability of the mutations to increase tumor immunogenicity through generation of tumor-specific antigens, which can then be targeted by the T-cell response.

This relationship between the mutational and neoantigen burden and patient outcomes has been described, but the role of the T-cell repertoire and how it relates to patient outcomes is less clear.

Hypothesizing that T-cell repertoire would be associated with survival in patients with NSCLC, he and his colleagues collected peripheral blood, normal lung, and tumor tissue, and performed T cell–receptor sequencing, among other analyses, in 398 patients.

“T cells recognize antigens through their T-cell receptor, as a result of which they undergo clonal expansion. Therefore, by sequencing the variable region of the T-cell receptor, one can gain insight into the T cells that are responding within the sample, as well as the overall T-cell repertoire,” he explained.

This provides information on T-cell density and richness, and thus on the diversity of the T-cell repertoire, he said, adding that it is possible to go beyond that and plot T cells based on their frequency in a sample to study clonality.

Since these T cells tend to expand clonally as a result of activation, uneven distribution would be associated with a reactive T-cell repertoire, as described by a high T-cell clonality.

An assessment to determine how the T-cell repertoire relates to clinical characteristics and response revealed a few interesting correlations. For example, adenocarcinomas tended to be more densely infiltrated than squamous cell carcinomas, smaller tumors were also more densely infiltrated by T cells than were their larger counterparts, and in smokers the T-cell repertoire appeared much more reactive than in nonsmokers.

“But ultimately, we didn’t see the [direct correlations between the T-cell repertoire and outcomes] we were hoping to see,” Dr. Reuben said, noting that this could be because of environmental influences.

“Obviously the lung is exposed to the outside environment, which could be masking some of the antitumor T-cell responses we were hoping to study,” he explained. “So we used a more holistic approach, integrating the peripheral blood and normal lung with tumor repertoire going forward.”
 

T cells in normal lung vs. tumor

Measuring the proportion of the T-cell repertoire that is shared in peripheral blood vs. normal lung and vs. tumor tissue showed that there is very little in common between them.

“However, when you compare the normal lung to the tumor, there’s much more homology in the T-cell repertoire,” he said, noting that, given the T-cell expansion resulting from antigenic stimulation, focusing on the most dominant cells in a sample highlights those most likely to be responding to antigens. “When we did that ... we saw even more of an enrichment in the homology between the normal lung and tumor T-cell repertoire, suggesting certain parallels in the ongoing immune responses across both these compartments.”

Further, T-cell density and diversity were actually higher in the tumor than in the normal lung in about two-thirds of patients, he said.

“However, surprisingly ... clonality appears to be much higher in the normal lung than in the tumor,” he added, noting that this was the case in about 75% of patients.

These findings raise three key questions:
 

Why is clonality higher in the normal lung?

T cells are not confined to a specific part of the host and are free to circulate, Dr. Reuben said.

“However, the closer you get to a site of inflammation, the higher the enrichment for T cells that are relevant to that specific site of inflammation, so you can use these statistical methods to enrich for T cells that are more relevant and try to subtract out T cells that are simply circulating through the organ,” he noted.

He and his colleagues used these methods and compared both normal lung and tumor to the peripheral blood, focusing only on clones that were statistically enriched in these two compartments “to really eliminate a lot of the background that may have been caused by the low-frequency T cells in these samples.”

When you look at the lung enriched T-cell repertoire between normal lung vs. tumor, the homology increases quite significantly, suggesting that by subtracting these T cells that are circulating through the host and not likely relevant to the antigenic response, you’re increasing the homology and further highlighting some of the aforementioned parallels in the ongoing immune responses between both sites, he said.

“Now if you look at clonality, there’s really no clear trend ... in the total T-cell repertoire or the enriched repertoire focusing on the normal lung, but if you look at the tumor, there’s a trend toward increased clonality in all patients – to the extent where you no longer see a difference in clonality between the normal lung and tumor, suggesting that this enrichment is allowing us to focus increasingly on T cells relevant to the antitumor response,” he added.

T-cell clonality is highly reliant on the ability of T cells to expand as a result of antigenic stimulation, and immune profiling showed that programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) were higher within the tumor, suggesting that there is some dysfunction on both sides of this interaction, which could also explain the lower clonality originally seen within the tumor, he said.
 

Why is the T-cell repertoire so similar across normal lung and tumor (and what are these T cells really recognizing)?

“Well, we performed whole-exome sequencing and it’s really no surprise that mutational load is substantial in the tumor, but what was surprising was the amount of mutations we detected in the normal lung,” Dr. Reuben said.

The number was lower than in the tumor, though still considerable, and included a large proportion that were shared mutations between the normal lung and the tumor, he noted.

A closer look at the shared mutations showed that they correlated positively with the proportion of shared dominant T cells between the normal lung and the tumor, suggesting that some of the shared T cells may be targeting shared mutations between the normal lung and the tumor. The correlation was weak, but statistically significant, so while it doesn’t account for all of the overlap, it likely accounts for some of the homology, he said.

In a paper published last year, Mark M Davis, PhD, of Stanford (Calif.) University and his colleagues went beyond standard analysis of the T-cell repertoire and identified residues specific to certain antigens in order to classify T cells based on their likely reactivity. Dr. Reuben and his colleagues collaborated with that group to determine whether T cells were predominantly viral or nonviral.

“If you focus on the normal lung and tumor, you don’t see much of a trend. In some patients there are more viral motifs, and in others are more nonviral motifs, but what was striking was the enrichment for viral motifs that we saw when we focused on the T cells that were shared between the normal lung and tumor,” Dr Reuben said.

In fact, 88% of patients had more viral motifs within their shared T cells vs. only 33% in the normal lung and 30% in tumor.

“So T cells that are shared may be recognizing a combination of shared mutations and/or viruses,” he explained.
 

How does the T-cell repertoire relate to outcomes?

A focus on the normal lung showed that patients with fewer T cells and lower clonality had better outcomes.

“What does this mean? It suggests that potentially, in these patients, the immune response in the lung is less distracted by outside pathogens and agents unrelated to the tumor, potentially providing the opportunity for a more focused antitumor T-cell response,” Dr. Reuben said, concluding that “T-cell density is higher, but clonality is lower in tumor vs. normal lung, there’s a substantial overlap in the T-cell repertoire between the normal lung and the tumor (including many T cells which may be reactive to shared mutations and/or viruses), and it seems like a more tumor-focused T-cell repertoire in the lung may be associated with improved outcomes.”

In an interview, Dr. Reuben said the findings have certain therapeutic implications, because most current therapies target the T-cell response whether by design or consequence.

“Considering the large proportion of T cells found in lung tumors which are unrelated to tumor responses, expansion of the wrong T cells – whether these target viruses or shared mutations between the normal lung and tumor – could potentially offer no benefit to the patient, because it would likely not contribute to eradicating their tumor,” he explained. “Furthermore, targeting T cells (through checkpoint blockade or TIL therapy) that are reactive to shared mutations could increase the potential for toxicity within these patients. Therefore, a better understanding of the T-cell repertoire in the lung is necessary to increase the specificity and success rates of current immunotherapies.”

Invited discussant, Antoni Ribas, MD, of the University of California, Los Angeles, suggested that the finding of a substantial number of shared T-cells is likely a baseline phenomenon, and that on-therapy biopsies in patients who respond to treatment would better separate and expand the T cells that responded from those that did not.

In fact, Dr. Reuben and his colleagues have expanded their research in this manner.

“We are now studying this phenomenon longitudinally in patients receiving checkpoint blockade to see how these factors evolve over the course of therapy,” he said.

Dr. Reuben reported having no disclosures. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or advisor for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.

sworcester@frontlinemedcom.com

SOURCE: Reuben A et al. Clinical Immuno-Oncology Symposium Abstract 140.

SAN FRANCISCO – An analysis of the T-cell repertoire in nearly 400 patients with stage I-III non–small cell lung cancer (NSCLC) suggests that patients with a more tumor-focused repertoire have better outcomes.

The findings, which suggest that patients with fewer T cells and with lower clonality in tumor-adjacent normal lung tissue fare better, could have implications for the use of tumor-infiltrating lymphocyte (TIL) therapy and checkpoint blockade – and possibly other therapies – in these patients, according to Alexandre Reuben, PhD, of the University of Texas MD Anderson Cancer Center, Houston.

Studying the T-cell repertoire in the lung can be rather “messy,” because many T cells may be responding to the outside environment, but comparing findings in the normal lung with those in tumor tissue helps to clarify things, Dr. Reuben said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
 

Why study the T-cell repertoire?

The successes seen with immune checkpoint blockade in recent years are largely a result of the ability of these therapies to enhance the antitumor T-cell response. Interestingly, checkpoint blockade works better in tumor types like lung cancer that have a high mutational load, Dr. Reuben said, explaining that this is largely attributable to the ability of the mutations to increase tumor immunogenicity through generation of tumor-specific antigens, which can then be targeted by the T-cell response.

This relationship between the mutational and neoantigen burden and patient outcomes has been described, but the role of the T-cell repertoire and how it relates to patient outcomes is less clear.

Hypothesizing that T-cell repertoire would be associated with survival in patients with NSCLC, he and his colleagues collected peripheral blood, normal lung, and tumor tissue, and performed T cell–receptor sequencing, among other analyses, in 398 patients.

“T cells recognize antigens through their T-cell receptor, as a result of which they undergo clonal expansion. Therefore, by sequencing the variable region of the T-cell receptor, one can gain insight into the T cells that are responding within the sample, as well as the overall T-cell repertoire,” he explained.

This provides information on T-cell density and richness, and thus on the diversity of the T-cell repertoire, he said, adding that it is possible to go beyond that and plot T cells based on their frequency in a sample to study clonality.

Since these T cells tend to expand clonally as a result of activation, uneven distribution would be associated with a reactive T-cell repertoire, as described by a high T-cell clonality.

An assessment to determine how the T-cell repertoire relates to clinical characteristics and response revealed a few interesting correlations. For example, adenocarcinomas tended to be more densely infiltrated than squamous cell carcinomas, smaller tumors were also more densely infiltrated by T cells than were their larger counterparts, and in smokers the T-cell repertoire appeared much more reactive than in nonsmokers.

“But ultimately, we didn’t see the [direct correlations between the T-cell repertoire and outcomes] we were hoping to see,” Dr. Reuben said, noting that this could be because of environmental influences.

“Obviously the lung is exposed to the outside environment, which could be masking some of the antitumor T-cell responses we were hoping to study,” he explained. “So we used a more holistic approach, integrating the peripheral blood and normal lung with tumor repertoire going forward.”
 

T cells in normal lung vs. tumor

Measuring the proportion of the T-cell repertoire that is shared in peripheral blood vs. normal lung and vs. tumor tissue showed that there is very little in common between them.

“However, when you compare the normal lung to the tumor, there’s much more homology in the T-cell repertoire,” he said, noting that, given the T-cell expansion resulting from antigenic stimulation, focusing on the most dominant cells in a sample highlights those most likely to be responding to antigens. “When we did that ... we saw even more of an enrichment in the homology between the normal lung and tumor T-cell repertoire, suggesting certain parallels in the ongoing immune responses across both these compartments.”

Further, T-cell density and diversity were actually higher in the tumor than in the normal lung in about two-thirds of patients, he said.

“However, surprisingly ... clonality appears to be much higher in the normal lung than in the tumor,” he added, noting that this was the case in about 75% of patients.

These findings raise three key questions:
 

Why is clonality higher in the normal lung?

T cells are not confined to a specific part of the host and are free to circulate, Dr. Reuben said.

“However, the closer you get to a site of inflammation, the higher the enrichment for T cells that are relevant to that specific site of inflammation, so you can use these statistical methods to enrich for T cells that are more relevant and try to subtract out T cells that are simply circulating through the organ,” he noted.

He and his colleagues used these methods and compared both normal lung and tumor to the peripheral blood, focusing only on clones that were statistically enriched in these two compartments “to really eliminate a lot of the background that may have been caused by the low-frequency T cells in these samples.”

When you look at the lung enriched T-cell repertoire between normal lung vs. tumor, the homology increases quite significantly, suggesting that by subtracting these T cells that are circulating through the host and not likely relevant to the antigenic response, you’re increasing the homology and further highlighting some of the aforementioned parallels in the ongoing immune responses between both sites, he said.

“Now if you look at clonality, there’s really no clear trend ... in the total T-cell repertoire or the enriched repertoire focusing on the normal lung, but if you look at the tumor, there’s a trend toward increased clonality in all patients – to the extent where you no longer see a difference in clonality between the normal lung and tumor, suggesting that this enrichment is allowing us to focus increasingly on T cells relevant to the antitumor response,” he added.

T-cell clonality is highly reliant on the ability of T cells to expand as a result of antigenic stimulation, and immune profiling showed that programmed cell death–1 (PD-1) and programmed death–ligand 1 (PD-L1) were higher within the tumor, suggesting that there is some dysfunction on both sides of this interaction, which could also explain the lower clonality originally seen within the tumor, he said.
 

Why is the T-cell repertoire so similar across normal lung and tumor (and what are these T cells really recognizing)?

“Well, we performed whole-exome sequencing and it’s really no surprise that mutational load is substantial in the tumor, but what was surprising was the amount of mutations we detected in the normal lung,” Dr. Reuben said.

The number was lower than in the tumor, though still considerable, and included a large proportion that were shared mutations between the normal lung and the tumor, he noted.

A closer look at the shared mutations showed that they correlated positively with the proportion of shared dominant T cells between the normal lung and the tumor, suggesting that some of the shared T cells may be targeting shared mutations between the normal lung and the tumor. The correlation was weak, but statistically significant, so while it doesn’t account for all of the overlap, it likely accounts for some of the homology, he said.

In a paper published last year, Mark M Davis, PhD, of Stanford (Calif.) University and his colleagues went beyond standard analysis of the T-cell repertoire and identified residues specific to certain antigens in order to classify T cells based on their likely reactivity. Dr. Reuben and his colleagues collaborated with that group to determine whether T cells were predominantly viral or nonviral.

“If you focus on the normal lung and tumor, you don’t see much of a trend. In some patients there are more viral motifs, and in others are more nonviral motifs, but what was striking was the enrichment for viral motifs that we saw when we focused on the T cells that were shared between the normal lung and tumor,” Dr Reuben said.

In fact, 88% of patients had more viral motifs within their shared T cells vs. only 33% in the normal lung and 30% in tumor.

“So T cells that are shared may be recognizing a combination of shared mutations and/or viruses,” he explained.
 

How does the T-cell repertoire relate to outcomes?

A focus on the normal lung showed that patients with fewer T cells and lower clonality had better outcomes.

“What does this mean? It suggests that potentially, in these patients, the immune response in the lung is less distracted by outside pathogens and agents unrelated to the tumor, potentially providing the opportunity for a more focused antitumor T-cell response,” Dr. Reuben said, concluding that “T-cell density is higher, but clonality is lower in tumor vs. normal lung, there’s a substantial overlap in the T-cell repertoire between the normal lung and the tumor (including many T cells which may be reactive to shared mutations and/or viruses), and it seems like a more tumor-focused T-cell repertoire in the lung may be associated with improved outcomes.”

In an interview, Dr. Reuben said the findings have certain therapeutic implications, because most current therapies target the T-cell response whether by design or consequence.

“Considering the large proportion of T cells found in lung tumors which are unrelated to tumor responses, expansion of the wrong T cells – whether these target viruses or shared mutations between the normal lung and tumor – could potentially offer no benefit to the patient, because it would likely not contribute to eradicating their tumor,” he explained. “Furthermore, targeting T cells (through checkpoint blockade or TIL therapy) that are reactive to shared mutations could increase the potential for toxicity within these patients. Therefore, a better understanding of the T-cell repertoire in the lung is necessary to increase the specificity and success rates of current immunotherapies.”

Invited discussant, Antoni Ribas, MD, of the University of California, Los Angeles, suggested that the finding of a substantial number of shared T-cells is likely a baseline phenomenon, and that on-therapy biopsies in patients who respond to treatment would better separate and expand the T cells that responded from those that did not.

In fact, Dr. Reuben and his colleagues have expanded their research in this manner.

“We are now studying this phenomenon longitudinally in patients receiving checkpoint blockade to see how these factors evolve over the course of therapy,” he said.

Dr. Reuben reported having no disclosures. Dr. Ribas owns stock in Advaxis, Arcus Ventures, Compugen, CytomX Therapeutics, Five Prime Therapeutics, FLX Bio, and Kite Pharma, and has served as a consultant or advisor for Amgen, Genentech/Roche, Merck, Novartis, and Pierre Fabre.

sworcester@frontlinemedcom.com

SOURCE: Reuben A et al. Clinical Immuno-Oncology Symposium Abstract 140.