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Older, cheaper drug formulation to remain available
The 140 mg capsules of Imbruvica® (ibrutinib) will remain on the market, according to Pharmacyclics LLC.
Pharmacyclics (an AbbVie company) and Janssen had planned to discontinue the capsules after introducing a single-tablet formulation of Imbruvica earlier this year.
However, the companies received negative feedback about the discontinuation and decided to keep the 140 mg capsules on the market.
In February, the US Food and Drug Administration (FDA) approved a single-tablet formulation of Imbruvica that is available in 4 doses—140 mg, 280 mg, 420 mg, and 560 mg.
Pharmacyclics and Janssen introduced this formulation to enable a once-a-day dosing regimen. The companies said the goal with the new formulation was to improve adherence because some patients had to take 3 or 4 pills every day to get the recommended dose of Imbruvica.
After introducing the new formulation, Pharmacyclics and Janssen planned to discontinue the 140 mg capsules.
Critics spoke out against this change in an article published in The Cancer Letter. They noted that discontinuing the old formulation would mean price increases for some patients. That’s because the single-tablet formulation of Imbruvica has the same price regardless of dose—$400 per tablet.
Patients on lower doses of Imbruvica would experience an increase in cost if they switched from the capsules to the tablet formulation. In fact, costs could triple for patients on the 140 mg dose.
Pharmacyclics argued that most patients on Imbruvica—those taking the 420 mg and 560 mg doses—would see no increase in out-of-pocket costs when transitioning to the single-tablet formulation. And patients on the 560 mg dose would likely see a decrease in their out-of-pocket costs.
However, critics pointed to results of a recent pilot study, which indicated that the recommended dose of Imbruvica for patients with chronic lymphocytic leukemia (CLL)—420 mg—may be too high. The results suggested that CLL patients could receive lower doses of Imbruvica without a reduction in efficacy.
Therefore, keeping the 140 mg capsules on the market could mean lower costs for some CLL patients.
In addition to voicing concerns about costs, the critics pointed out that discontinuing the 140 mg capsules of Imbruvica would make it more difficult to adjust patients’ doses when needed.
Pharmacyclics said its YOU&i™ Dose Exchange Program can aid healthcare professionals in adjusting doses before patients have finished their current pack of Imbruvica. Patients would receive a “rapid shipment” of their new dose at no additional cost.
But the critics said this program “creates a barrier to optimal prescribing for some patients” and urged the FDA to review the safety of the program.
Roughly a month after the critics made this recommendation in The Cancer Letter article, Pharmacyclics announced that the 140 mg capsules of Imbruvica would remain on the market.
The 140 mg capsules of Imbruvica® (ibrutinib) will remain on the market, according to Pharmacyclics LLC.
Pharmacyclics (an AbbVie company) and Janssen had planned to discontinue the capsules after introducing a single-tablet formulation of Imbruvica earlier this year.
However, the companies received negative feedback about the discontinuation and decided to keep the 140 mg capsules on the market.
In February, the US Food and Drug Administration (FDA) approved a single-tablet formulation of Imbruvica that is available in 4 doses—140 mg, 280 mg, 420 mg, and 560 mg.
Pharmacyclics and Janssen introduced this formulation to enable a once-a-day dosing regimen. The companies said the goal with the new formulation was to improve adherence because some patients had to take 3 or 4 pills every day to get the recommended dose of Imbruvica.
After introducing the new formulation, Pharmacyclics and Janssen planned to discontinue the 140 mg capsules.
Critics spoke out against this change in an article published in The Cancer Letter. They noted that discontinuing the old formulation would mean price increases for some patients. That’s because the single-tablet formulation of Imbruvica has the same price regardless of dose—$400 per tablet.
Patients on lower doses of Imbruvica would experience an increase in cost if they switched from the capsules to the tablet formulation. In fact, costs could triple for patients on the 140 mg dose.
Pharmacyclics argued that most patients on Imbruvica—those taking the 420 mg and 560 mg doses—would see no increase in out-of-pocket costs when transitioning to the single-tablet formulation. And patients on the 560 mg dose would likely see a decrease in their out-of-pocket costs.
However, critics pointed to results of a recent pilot study, which indicated that the recommended dose of Imbruvica for patients with chronic lymphocytic leukemia (CLL)—420 mg—may be too high. The results suggested that CLL patients could receive lower doses of Imbruvica without a reduction in efficacy.
Therefore, keeping the 140 mg capsules on the market could mean lower costs for some CLL patients.
In addition to voicing concerns about costs, the critics pointed out that discontinuing the 140 mg capsules of Imbruvica would make it more difficult to adjust patients’ doses when needed.
Pharmacyclics said its YOU&i™ Dose Exchange Program can aid healthcare professionals in adjusting doses before patients have finished their current pack of Imbruvica. Patients would receive a “rapid shipment” of their new dose at no additional cost.
But the critics said this program “creates a barrier to optimal prescribing for some patients” and urged the FDA to review the safety of the program.
Roughly a month after the critics made this recommendation in The Cancer Letter article, Pharmacyclics announced that the 140 mg capsules of Imbruvica would remain on the market.
The 140 mg capsules of Imbruvica® (ibrutinib) will remain on the market, according to Pharmacyclics LLC.
Pharmacyclics (an AbbVie company) and Janssen had planned to discontinue the capsules after introducing a single-tablet formulation of Imbruvica earlier this year.
However, the companies received negative feedback about the discontinuation and decided to keep the 140 mg capsules on the market.
In February, the US Food and Drug Administration (FDA) approved a single-tablet formulation of Imbruvica that is available in 4 doses—140 mg, 280 mg, 420 mg, and 560 mg.
Pharmacyclics and Janssen introduced this formulation to enable a once-a-day dosing regimen. The companies said the goal with the new formulation was to improve adherence because some patients had to take 3 or 4 pills every day to get the recommended dose of Imbruvica.
After introducing the new formulation, Pharmacyclics and Janssen planned to discontinue the 140 mg capsules.
Critics spoke out against this change in an article published in The Cancer Letter. They noted that discontinuing the old formulation would mean price increases for some patients. That’s because the single-tablet formulation of Imbruvica has the same price regardless of dose—$400 per tablet.
Patients on lower doses of Imbruvica would experience an increase in cost if they switched from the capsules to the tablet formulation. In fact, costs could triple for patients on the 140 mg dose.
Pharmacyclics argued that most patients on Imbruvica—those taking the 420 mg and 560 mg doses—would see no increase in out-of-pocket costs when transitioning to the single-tablet formulation. And patients on the 560 mg dose would likely see a decrease in their out-of-pocket costs.
However, critics pointed to results of a recent pilot study, which indicated that the recommended dose of Imbruvica for patients with chronic lymphocytic leukemia (CLL)—420 mg—may be too high. The results suggested that CLL patients could receive lower doses of Imbruvica without a reduction in efficacy.
Therefore, keeping the 140 mg capsules on the market could mean lower costs for some CLL patients.
In addition to voicing concerns about costs, the critics pointed out that discontinuing the 140 mg capsules of Imbruvica would make it more difficult to adjust patients’ doses when needed.
Pharmacyclics said its YOU&i™ Dose Exchange Program can aid healthcare professionals in adjusting doses before patients have finished their current pack of Imbruvica. Patients would receive a “rapid shipment” of their new dose at no additional cost.
But the critics said this program “creates a barrier to optimal prescribing for some patients” and urged the FDA to review the safety of the program.
Roughly a month after the critics made this recommendation in The Cancer Letter article, Pharmacyclics announced that the 140 mg capsules of Imbruvica would remain on the market.
Regimen can improve DFS in newly diagnosed T-ALL
The addition of nelarabine can improve treatment outcomes for certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to a phase 3 trial.
Patients with newly diagnosed, intermediate- or high-risk T-ALL had a significant improvement in 4-year disease-free survival (DFS) if they received nelarabine in addition to chemotherapy and cranial irradiation.
The DFS benefit with nelarabine was significant for patients who received high-dose methotrexate but not for those who received escalating-dose methotrexate.
This study also included patients with T-cell lymphoblastic lymphoma (T-LL), and they did not experience an improvement in DFS with the addition of nelarabine.
Kimberly Dunsmore, MD, of Virginia Tech Carilion School of Medicine in Roanoke, presented these results in a press briefing in advance of the 2018 ASCO Annual Meeting. Additional results are scheduled to be presented at the meeting as abstract 10500.
This research was supported by the National Cancer Institute/National Institutes of Health and St. Baldrick’s Foundation. The researchers’ disclosures are listed with the abstract.
Patients and treatment
The trial enrolled 1895 patients, ages 1 to 30, who were newly diagnosed with T-ALL (94%) or T-LL (6%).
Patients received standard 4-drug induction chemotherapy, and 1307 of these patients were then randomized to 1 of 4 treatment arms.
Regardless of which arm they were randomized to, patients received an 11-drug chemotherapy regimen—the augmented Berlin-Frankfurt-Munster regimen. Intermediate- and high-risk patients in all 4 arms also received cranial irradiation.
In the first treatment arm, T-LL (n=58) and T-ALL (n=372) patients received escalating-dose methotrexate without leucovorin rescue and pegaspargase (C-MTX).
In the second treatment arm, patients with intermediate- and high-risk T-ALL (n=147) and T-LL (n=60) received C-MTX plus nelarabine (six 5-day courses at 650 mg/m2/day).
In the third arm, T-ALL patients (n=451) received high-dose methotrexate with leucovorin rescue (HD-MTX). T-LL patients were not eligible for this arm or the fourth treatment arm.
In the fourth arm, intermediate- and high-risk T-ALL patients (n=219) received HD-MTX and nelarabine (same schedule as above). This included 43 T-ALL patients who had induction failure and were assigned to this arm non-randomly.
Results
For T-ALL patients, the 4-year disease-free survival (DFS) rate was 84%, and the 4-year overall survival rate was 90%.
There was a significant improvement in DFS for T-ALL patients who received nelarabine compared to those who did not—89% and 83%, respectively (P=0.0332).
“Historically, about 80% of people [with T-ALL] live at least 4 years after being treated for their disease, but we felt we could and must do better,” Dr Dunsmore said. “Our trial shows that we could further increase survival rates by about 10%, which is very encouraging.”
Dr Dunsmore also noted that patients who received nelarabine had fewer central nervous system relapses.
Among T-ALL patients who received C-MTX, there was no significant difference in DFS for those who received nelarabine and those who did not—92% and 90%, respectively (P=0.3825).
However, for patients who received HD-MTX, the difference in DFS was significant. The DFS rate was 86% in patients who received nelarabine and 78% in those who did not (P=0.024).
For the T-ALL patients who failed induction and were assigned to HD-MTX and nelarabine, the 4-year DFS rate was 55%.
Patients with T-LL did not benefit from the addition of nelarabine. The 4-year DFS rate was 85% in the nelarabine recipients and 89% in non-recipients (P=0.2788).
There were no significant differences in overall toxicity or peripheral neurotoxicity between the treatment arms.
Dr Dunsmore said the next step with this research will be to examine the implications and potential benefits of using nelarabine in treatment protocols that do not include cranial radiation.
The addition of nelarabine can improve treatment outcomes for certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to a phase 3 trial.
Patients with newly diagnosed, intermediate- or high-risk T-ALL had a significant improvement in 4-year disease-free survival (DFS) if they received nelarabine in addition to chemotherapy and cranial irradiation.
The DFS benefit with nelarabine was significant for patients who received high-dose methotrexate but not for those who received escalating-dose methotrexate.
This study also included patients with T-cell lymphoblastic lymphoma (T-LL), and they did not experience an improvement in DFS with the addition of nelarabine.
Kimberly Dunsmore, MD, of Virginia Tech Carilion School of Medicine in Roanoke, presented these results in a press briefing in advance of the 2018 ASCO Annual Meeting. Additional results are scheduled to be presented at the meeting as abstract 10500.
This research was supported by the National Cancer Institute/National Institutes of Health and St. Baldrick’s Foundation. The researchers’ disclosures are listed with the abstract.
Patients and treatment
The trial enrolled 1895 patients, ages 1 to 30, who were newly diagnosed with T-ALL (94%) or T-LL (6%).
Patients received standard 4-drug induction chemotherapy, and 1307 of these patients were then randomized to 1 of 4 treatment arms.
Regardless of which arm they were randomized to, patients received an 11-drug chemotherapy regimen—the augmented Berlin-Frankfurt-Munster regimen. Intermediate- and high-risk patients in all 4 arms also received cranial irradiation.
In the first treatment arm, T-LL (n=58) and T-ALL (n=372) patients received escalating-dose methotrexate without leucovorin rescue and pegaspargase (C-MTX).
In the second treatment arm, patients with intermediate- and high-risk T-ALL (n=147) and T-LL (n=60) received C-MTX plus nelarabine (six 5-day courses at 650 mg/m2/day).
In the third arm, T-ALL patients (n=451) received high-dose methotrexate with leucovorin rescue (HD-MTX). T-LL patients were not eligible for this arm or the fourth treatment arm.
In the fourth arm, intermediate- and high-risk T-ALL patients (n=219) received HD-MTX and nelarabine (same schedule as above). This included 43 T-ALL patients who had induction failure and were assigned to this arm non-randomly.
Results
For T-ALL patients, the 4-year disease-free survival (DFS) rate was 84%, and the 4-year overall survival rate was 90%.
There was a significant improvement in DFS for T-ALL patients who received nelarabine compared to those who did not—89% and 83%, respectively (P=0.0332).
“Historically, about 80% of people [with T-ALL] live at least 4 years after being treated for their disease, but we felt we could and must do better,” Dr Dunsmore said. “Our trial shows that we could further increase survival rates by about 10%, which is very encouraging.”
Dr Dunsmore also noted that patients who received nelarabine had fewer central nervous system relapses.
Among T-ALL patients who received C-MTX, there was no significant difference in DFS for those who received nelarabine and those who did not—92% and 90%, respectively (P=0.3825).
However, for patients who received HD-MTX, the difference in DFS was significant. The DFS rate was 86% in patients who received nelarabine and 78% in those who did not (P=0.024).
For the T-ALL patients who failed induction and were assigned to HD-MTX and nelarabine, the 4-year DFS rate was 55%.
Patients with T-LL did not benefit from the addition of nelarabine. The 4-year DFS rate was 85% in the nelarabine recipients and 89% in non-recipients (P=0.2788).
There were no significant differences in overall toxicity or peripheral neurotoxicity between the treatment arms.
Dr Dunsmore said the next step with this research will be to examine the implications and potential benefits of using nelarabine in treatment protocols that do not include cranial radiation.
The addition of nelarabine can improve treatment outcomes for certain patients with T-cell acute lymphoblastic leukemia (T-ALL), according to a phase 3 trial.
Patients with newly diagnosed, intermediate- or high-risk T-ALL had a significant improvement in 4-year disease-free survival (DFS) if they received nelarabine in addition to chemotherapy and cranial irradiation.
The DFS benefit with nelarabine was significant for patients who received high-dose methotrexate but not for those who received escalating-dose methotrexate.
This study also included patients with T-cell lymphoblastic lymphoma (T-LL), and they did not experience an improvement in DFS with the addition of nelarabine.
Kimberly Dunsmore, MD, of Virginia Tech Carilion School of Medicine in Roanoke, presented these results in a press briefing in advance of the 2018 ASCO Annual Meeting. Additional results are scheduled to be presented at the meeting as abstract 10500.
This research was supported by the National Cancer Institute/National Institutes of Health and St. Baldrick’s Foundation. The researchers’ disclosures are listed with the abstract.
Patients and treatment
The trial enrolled 1895 patients, ages 1 to 30, who were newly diagnosed with T-ALL (94%) or T-LL (6%).
Patients received standard 4-drug induction chemotherapy, and 1307 of these patients were then randomized to 1 of 4 treatment arms.
Regardless of which arm they were randomized to, patients received an 11-drug chemotherapy regimen—the augmented Berlin-Frankfurt-Munster regimen. Intermediate- and high-risk patients in all 4 arms also received cranial irradiation.
In the first treatment arm, T-LL (n=58) and T-ALL (n=372) patients received escalating-dose methotrexate without leucovorin rescue and pegaspargase (C-MTX).
In the second treatment arm, patients with intermediate- and high-risk T-ALL (n=147) and T-LL (n=60) received C-MTX plus nelarabine (six 5-day courses at 650 mg/m2/day).
In the third arm, T-ALL patients (n=451) received high-dose methotrexate with leucovorin rescue (HD-MTX). T-LL patients were not eligible for this arm or the fourth treatment arm.
In the fourth arm, intermediate- and high-risk T-ALL patients (n=219) received HD-MTX and nelarabine (same schedule as above). This included 43 T-ALL patients who had induction failure and were assigned to this arm non-randomly.
Results
For T-ALL patients, the 4-year disease-free survival (DFS) rate was 84%, and the 4-year overall survival rate was 90%.
There was a significant improvement in DFS for T-ALL patients who received nelarabine compared to those who did not—89% and 83%, respectively (P=0.0332).
“Historically, about 80% of people [with T-ALL] live at least 4 years after being treated for their disease, but we felt we could and must do better,” Dr Dunsmore said. “Our trial shows that we could further increase survival rates by about 10%, which is very encouraging.”
Dr Dunsmore also noted that patients who received nelarabine had fewer central nervous system relapses.
Among T-ALL patients who received C-MTX, there was no significant difference in DFS for those who received nelarabine and those who did not—92% and 90%, respectively (P=0.3825).
However, for patients who received HD-MTX, the difference in DFS was significant. The DFS rate was 86% in patients who received nelarabine and 78% in those who did not (P=0.024).
For the T-ALL patients who failed induction and were assigned to HD-MTX and nelarabine, the 4-year DFS rate was 55%.
Patients with T-LL did not benefit from the addition of nelarabine. The 4-year DFS rate was 85% in the nelarabine recipients and 89% in non-recipients (P=0.2788).
There were no significant differences in overall toxicity or peripheral neurotoxicity between the treatment arms.
Dr Dunsmore said the next step with this research will be to examine the implications and potential benefits of using nelarabine in treatment protocols that do not include cranial radiation.
Umbralisib has ‘distinct’ safety profile
Phase 1 trial results suggest umbralisib, a PI3Kδ/CK1ε inhibitor, can be safe and active in patients with relapsed or refractory B-cell malignancies.
Researchers said the safety profile of umbralisib “was distinct from that of other PI3Kδ inhibitors,” as it produced few immune-mediated adverse events (AEs).
Umbralisib also produced an objective response rate of 37% in the entire study cohort, 80% in patients with chronic lymphocytic leukemia (CLL), 53% in patients with follicular lymphoma (FL), and 31% in patients with diffuse large B-cell lymphoma (DLBCL).
These results were published in The Lancet Oncology. The study was sponsored by TG Therapeutics, Inc.
The trial enrolled 90 patients between January 17, 2013, and January 14, 2016.
There were 24 patients with CLL, 22 with FL, 16 with DLBCL, 11 with Hodgkin lymphoma, 6 with mantle cell lymphoma, 5 with marginal zone lymphoma, 3 with Waldenstrom’s macroglobulinemia, 2 with T-cell lymphoma, and 1 with hairy cell leukemia.
The median number of prior therapies was 3 (range, 2-5), and 49% of patients were refractory to previous therapy.
Treatment
Patients took umbralisib once daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.
Initially, patients took the drug in a fasting state at doses of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.
In April 2014, the researchers did a second dose-escalation with a micronized formulation of umbralisib, taken with food, at doses of 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.
In August, 2014, all patients who were still on the study transitioned to the 800 mg dose of the micronized formulation. This was the recommended phase 2 dose.
At the data cutoff in November 2016, 44 patients (49%) had received umbralisib for more than 6 cycles, and 23 (26%) had received the drug for more than 12 cycles. Thirteen patients (14%) were still taking umbralisib at the end of the study.
Most patients who stopped treatment did so because of disease progression (n=50, 56%) or AEs (n=9, 10%).
“We are pleased to have treated the first patient ever with umbralisib over 5 years ago and believe it has an important place in the treatment landscape for patients with hematologic malignancies,” said study author Howard A. Burris, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee.
“Several patients from this phase 1 study are still on study today, approaching 5 years of continuous daily therapy, speaking to both the safety and efficacy profile of this unique agent.”
Safety
Dose-limiting toxicities (DLTs) occurred in 4 patients. One DLT was grade 3 maculopapular rash in a patient receiving the 800 mg dose of the initial formulation.
Another DLT was grade 3 hypokalemia in a patient receiving 1800 mg of the initial formulation. A third DLT was grade 3 fatigue, which occurred in 2 patients receiving 1800 mg of the micronized formulation.
Because of these toxicities, the maximum tolerated dose was 1200 mg of the micronized formulation.
The most common treatment-emergent AEs were diarrhea (43%), nausea (42%), and fatigue (31%). The most common grade 3/4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).
Serious AEs considered at least possibly related to umbralisib were pneumonia (3%), lung infection (1%), febrile neutropenia (1%), and colitis (2%).
Treatment discontinuation due to AEs considered at least possibly related to umbralisib occurred in 6 patients (7%). Two patients had grade 3 colitis, 2 had increased ALT/AST (grade 1 and grade 4), 1 had grade 2 diarrhea, and 1 had grade 3 fatigue.
There were no treatment-related deaths.
The researchers said the safety profile of umbralisib was distinct from that of other PI3Kδ inhibitors, as patients in this trial had fewer occurrences of autoimmune-like toxicities, such as colitis.
“Preclinically, umbralisib has a very unique profile, selectively inhibiting both PI3Kδ and CK1ε,” said study author Owen O’Connor, MD, PhD, of Columbia Presbyterian Medical Center in New York, New York.
“The clinical results in this paper support our thesis that the differentiated preclinical profile explains the differences seen in the clinic between umbralisib and the other PI3Kδ inhibitors.”
Response
The objective response rate was 37%, with 33 patients achieving a response and 3 patients having a complete response (CR).
Sixteen CLL patients responded (80%), all with partial responses (PRs). Four DLBCL patients responded (31%), all with PRs. And 9 FL patients responded (53%), 2 with CRs.
The remaining CR occurred in a Hodgkin lymphoma patient, and this was the only response in this patient group.
One patient with marginal zone lymphoma had a PR, as did 1 patient with mantle cell lymphoma. All other patients had stable disease or progressed.
The mean duration of response was 13.4 months in the CLL patients, 6.4 months in the DLBCL patients, and 9.3 months in the FL patients.
Phase 1 trial results suggest umbralisib, a PI3Kδ/CK1ε inhibitor, can be safe and active in patients with relapsed or refractory B-cell malignancies.
Researchers said the safety profile of umbralisib “was distinct from that of other PI3Kδ inhibitors,” as it produced few immune-mediated adverse events (AEs).
Umbralisib also produced an objective response rate of 37% in the entire study cohort, 80% in patients with chronic lymphocytic leukemia (CLL), 53% in patients with follicular lymphoma (FL), and 31% in patients with diffuse large B-cell lymphoma (DLBCL).
These results were published in The Lancet Oncology. The study was sponsored by TG Therapeutics, Inc.
The trial enrolled 90 patients between January 17, 2013, and January 14, 2016.
There were 24 patients with CLL, 22 with FL, 16 with DLBCL, 11 with Hodgkin lymphoma, 6 with mantle cell lymphoma, 5 with marginal zone lymphoma, 3 with Waldenstrom’s macroglobulinemia, 2 with T-cell lymphoma, and 1 with hairy cell leukemia.
The median number of prior therapies was 3 (range, 2-5), and 49% of patients were refractory to previous therapy.
Treatment
Patients took umbralisib once daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.
Initially, patients took the drug in a fasting state at doses of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.
In April 2014, the researchers did a second dose-escalation with a micronized formulation of umbralisib, taken with food, at doses of 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.
In August, 2014, all patients who were still on the study transitioned to the 800 mg dose of the micronized formulation. This was the recommended phase 2 dose.
At the data cutoff in November 2016, 44 patients (49%) had received umbralisib for more than 6 cycles, and 23 (26%) had received the drug for more than 12 cycles. Thirteen patients (14%) were still taking umbralisib at the end of the study.
Most patients who stopped treatment did so because of disease progression (n=50, 56%) or AEs (n=9, 10%).
“We are pleased to have treated the first patient ever with umbralisib over 5 years ago and believe it has an important place in the treatment landscape for patients with hematologic malignancies,” said study author Howard A. Burris, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee.
“Several patients from this phase 1 study are still on study today, approaching 5 years of continuous daily therapy, speaking to both the safety and efficacy profile of this unique agent.”
Safety
Dose-limiting toxicities (DLTs) occurred in 4 patients. One DLT was grade 3 maculopapular rash in a patient receiving the 800 mg dose of the initial formulation.
Another DLT was grade 3 hypokalemia in a patient receiving 1800 mg of the initial formulation. A third DLT was grade 3 fatigue, which occurred in 2 patients receiving 1800 mg of the micronized formulation.
Because of these toxicities, the maximum tolerated dose was 1200 mg of the micronized formulation.
The most common treatment-emergent AEs were diarrhea (43%), nausea (42%), and fatigue (31%). The most common grade 3/4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).
Serious AEs considered at least possibly related to umbralisib were pneumonia (3%), lung infection (1%), febrile neutropenia (1%), and colitis (2%).
Treatment discontinuation due to AEs considered at least possibly related to umbralisib occurred in 6 patients (7%). Two patients had grade 3 colitis, 2 had increased ALT/AST (grade 1 and grade 4), 1 had grade 2 diarrhea, and 1 had grade 3 fatigue.
There were no treatment-related deaths.
The researchers said the safety profile of umbralisib was distinct from that of other PI3Kδ inhibitors, as patients in this trial had fewer occurrences of autoimmune-like toxicities, such as colitis.
“Preclinically, umbralisib has a very unique profile, selectively inhibiting both PI3Kδ and CK1ε,” said study author Owen O’Connor, MD, PhD, of Columbia Presbyterian Medical Center in New York, New York.
“The clinical results in this paper support our thesis that the differentiated preclinical profile explains the differences seen in the clinic between umbralisib and the other PI3Kδ inhibitors.”
Response
The objective response rate was 37%, with 33 patients achieving a response and 3 patients having a complete response (CR).
Sixteen CLL patients responded (80%), all with partial responses (PRs). Four DLBCL patients responded (31%), all with PRs. And 9 FL patients responded (53%), 2 with CRs.
The remaining CR occurred in a Hodgkin lymphoma patient, and this was the only response in this patient group.
One patient with marginal zone lymphoma had a PR, as did 1 patient with mantle cell lymphoma. All other patients had stable disease or progressed.
The mean duration of response was 13.4 months in the CLL patients, 6.4 months in the DLBCL patients, and 9.3 months in the FL patients.
Phase 1 trial results suggest umbralisib, a PI3Kδ/CK1ε inhibitor, can be safe and active in patients with relapsed or refractory B-cell malignancies.
Researchers said the safety profile of umbralisib “was distinct from that of other PI3Kδ inhibitors,” as it produced few immune-mediated adverse events (AEs).
Umbralisib also produced an objective response rate of 37% in the entire study cohort, 80% in patients with chronic lymphocytic leukemia (CLL), 53% in patients with follicular lymphoma (FL), and 31% in patients with diffuse large B-cell lymphoma (DLBCL).
These results were published in The Lancet Oncology. The study was sponsored by TG Therapeutics, Inc.
The trial enrolled 90 patients between January 17, 2013, and January 14, 2016.
There were 24 patients with CLL, 22 with FL, 16 with DLBCL, 11 with Hodgkin lymphoma, 6 with mantle cell lymphoma, 5 with marginal zone lymphoma, 3 with Waldenstrom’s macroglobulinemia, 2 with T-cell lymphoma, and 1 with hairy cell leukemia.
The median number of prior therapies was 3 (range, 2-5), and 49% of patients were refractory to previous therapy.
Treatment
Patients took umbralisib once daily in 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent.
Initially, patients took the drug in a fasting state at doses of 50 mg, 100 mg, 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.
In April 2014, the researchers did a second dose-escalation with a micronized formulation of umbralisib, taken with food, at doses of 200 mg, 400 mg, 800 mg, 1200 mg, or 1800 mg.
In August, 2014, all patients who were still on the study transitioned to the 800 mg dose of the micronized formulation. This was the recommended phase 2 dose.
At the data cutoff in November 2016, 44 patients (49%) had received umbralisib for more than 6 cycles, and 23 (26%) had received the drug for more than 12 cycles. Thirteen patients (14%) were still taking umbralisib at the end of the study.
Most patients who stopped treatment did so because of disease progression (n=50, 56%) or AEs (n=9, 10%).
“We are pleased to have treated the first patient ever with umbralisib over 5 years ago and believe it has an important place in the treatment landscape for patients with hematologic malignancies,” said study author Howard A. Burris, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee.
“Several patients from this phase 1 study are still on study today, approaching 5 years of continuous daily therapy, speaking to both the safety and efficacy profile of this unique agent.”
Safety
Dose-limiting toxicities (DLTs) occurred in 4 patients. One DLT was grade 3 maculopapular rash in a patient receiving the 800 mg dose of the initial formulation.
Another DLT was grade 3 hypokalemia in a patient receiving 1800 mg of the initial formulation. A third DLT was grade 3 fatigue, which occurred in 2 patients receiving 1800 mg of the micronized formulation.
Because of these toxicities, the maximum tolerated dose was 1200 mg of the micronized formulation.
The most common treatment-emergent AEs were diarrhea (43%), nausea (42%), and fatigue (31%). The most common grade 3/4 AEs were neutropenia (13%), anemia (9%), and thrombocytopenia (7%).
Serious AEs considered at least possibly related to umbralisib were pneumonia (3%), lung infection (1%), febrile neutropenia (1%), and colitis (2%).
Treatment discontinuation due to AEs considered at least possibly related to umbralisib occurred in 6 patients (7%). Two patients had grade 3 colitis, 2 had increased ALT/AST (grade 1 and grade 4), 1 had grade 2 diarrhea, and 1 had grade 3 fatigue.
There were no treatment-related deaths.
The researchers said the safety profile of umbralisib was distinct from that of other PI3Kδ inhibitors, as patients in this trial had fewer occurrences of autoimmune-like toxicities, such as colitis.
“Preclinically, umbralisib has a very unique profile, selectively inhibiting both PI3Kδ and CK1ε,” said study author Owen O’Connor, MD, PhD, of Columbia Presbyterian Medical Center in New York, New York.
“The clinical results in this paper support our thesis that the differentiated preclinical profile explains the differences seen in the clinic between umbralisib and the other PI3Kδ inhibitors.”
Response
The objective response rate was 37%, with 33 patients achieving a response and 3 patients having a complete response (CR).
Sixteen CLL patients responded (80%), all with partial responses (PRs). Four DLBCL patients responded (31%), all with PRs. And 9 FL patients responded (53%), 2 with CRs.
The remaining CR occurred in a Hodgkin lymphoma patient, and this was the only response in this patient group.
One patient with marginal zone lymphoma had a PR, as did 1 patient with mantle cell lymphoma. All other patients had stable disease or progressed.
The mean duration of response was 13.4 months in the CLL patients, 6.4 months in the DLBCL patients, and 9.3 months in the FL patients.
Team identifies new prognostic factor for MF
New research suggests DNA sequencing can reveal which patients with early stage mycosis fungoides (MF) will develop aggressive disease.
By sequencing the T-cell receptor beta gene (TCRB) in skin biopsies from MF patients, investigators were able to measure the tumor clone frequency (TCF), or the percentage of all T cells that represent the MF clone.
The researchers found the TCF could predict progression-free survival (PFS) and overall survival (OS).
In fact, for patients with early stage MF, TCF was a stronger predictor of PFS than other established prognostic factors.
“While more work needs to be done, we think this approach has the potential to prospectively identify a subgroup of patients who are destined to develop aggressive, life-threatening disease and treat them in a more aggressive fashion with the intent to better manage and, ideally, cure their cancer,” said Thomas Kupper, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“At the same time, we believe we can provide reassurance to patients with a low-risk (low TCF) profile that they are likely to survive indefinitely with conventional conservative therapies. As a physician who has treated this disease for decades, I am excited to be involved with work that so directly and profoundly affects the care and management of these patients.”
Dr Kupper and his colleagues described this work in Science Translational Medicine.
The researchers had previously published a study showing that high-throughput sequencing of the TCRB gene was an accurate way to diagnose cutaneous T-cell lymphoma (CTCL), including MF.
With the current study, the investigators set out to determine if the method could be used to predict progression and survival in patients with CTCL.
The team sequenced TCRB in lesional skin biopsies from 309 CTCL patients, most of whom had MF. The discovery cohort had 208 patients (177 with MF), and the validation cohort had 101 patients (87 with MF).
The sequencing produced a snapshot of the TCRB genes from a large number of cells at the site of the lesion. And the researchers could use this to measure TCF.
The team tested the association of TCF with prognosis in all CTCL patients in the discovery cohort and found a TCF greater than 25% in the skin was significantly associated with reduced PFS (P<0.001) and OS (P<0.001). Results were similar in the validation cohort (P<0.001 for PFS and OS).
The investigators also found that TCF was significantly associated with PFS (P<0.001) and OS (P<0.001) in MF patients but not in patients with Sézary syndrome. The team noted that they did not assess the predictive value of TCF in the blood of Sézary patients.
In a multivariable analysis, TCF was still significantly associated with PFS (P<0.001) and OS (P<0.001) in the MF patients.
The researchers also assessed potential prognostic variables in the early stage MF patients and found a TCF greater than 25% was a stronger predictor of PFS than any other established prognostic factor. This includes disease stage, presence of plaques, elevated lactate dehydrogenase, age, large-cell transformation, and CLIPI score.
“In reviewing the results, 2 different patients could have identical-looking skin lesions, but one might have a TCF of 8%, and one would have a TCF of 40%,” Dr Kupper noted. “The latter patient was highly likely to progress—something we would never have been able to predict before this discovery.”
“The TCF was independent of how thick or thin the skin lesions were. Most importantly, compared to all other currently used means of trying to predict which patients would progress, TCF was by far the most sensitive and specific.”
The high-throughput sequencing in this study was performed using ImmunoSEQ, an assay developed by Adaptive Biotechnologies. The company did not sponsor the study, but company employees were involved in the research.
New research suggests DNA sequencing can reveal which patients with early stage mycosis fungoides (MF) will develop aggressive disease.
By sequencing the T-cell receptor beta gene (TCRB) in skin biopsies from MF patients, investigators were able to measure the tumor clone frequency (TCF), or the percentage of all T cells that represent the MF clone.
The researchers found the TCF could predict progression-free survival (PFS) and overall survival (OS).
In fact, for patients with early stage MF, TCF was a stronger predictor of PFS than other established prognostic factors.
“While more work needs to be done, we think this approach has the potential to prospectively identify a subgroup of patients who are destined to develop aggressive, life-threatening disease and treat them in a more aggressive fashion with the intent to better manage and, ideally, cure their cancer,” said Thomas Kupper, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“At the same time, we believe we can provide reassurance to patients with a low-risk (low TCF) profile that they are likely to survive indefinitely with conventional conservative therapies. As a physician who has treated this disease for decades, I am excited to be involved with work that so directly and profoundly affects the care and management of these patients.”
Dr Kupper and his colleagues described this work in Science Translational Medicine.
The researchers had previously published a study showing that high-throughput sequencing of the TCRB gene was an accurate way to diagnose cutaneous T-cell lymphoma (CTCL), including MF.
With the current study, the investigators set out to determine if the method could be used to predict progression and survival in patients with CTCL.
The team sequenced TCRB in lesional skin biopsies from 309 CTCL patients, most of whom had MF. The discovery cohort had 208 patients (177 with MF), and the validation cohort had 101 patients (87 with MF).
The sequencing produced a snapshot of the TCRB genes from a large number of cells at the site of the lesion. And the researchers could use this to measure TCF.
The team tested the association of TCF with prognosis in all CTCL patients in the discovery cohort and found a TCF greater than 25% in the skin was significantly associated with reduced PFS (P<0.001) and OS (P<0.001). Results were similar in the validation cohort (P<0.001 for PFS and OS).
The investigators also found that TCF was significantly associated with PFS (P<0.001) and OS (P<0.001) in MF patients but not in patients with Sézary syndrome. The team noted that they did not assess the predictive value of TCF in the blood of Sézary patients.
In a multivariable analysis, TCF was still significantly associated with PFS (P<0.001) and OS (P<0.001) in the MF patients.
The researchers also assessed potential prognostic variables in the early stage MF patients and found a TCF greater than 25% was a stronger predictor of PFS than any other established prognostic factor. This includes disease stage, presence of plaques, elevated lactate dehydrogenase, age, large-cell transformation, and CLIPI score.
“In reviewing the results, 2 different patients could have identical-looking skin lesions, but one might have a TCF of 8%, and one would have a TCF of 40%,” Dr Kupper noted. “The latter patient was highly likely to progress—something we would never have been able to predict before this discovery.”
“The TCF was independent of how thick or thin the skin lesions were. Most importantly, compared to all other currently used means of trying to predict which patients would progress, TCF was by far the most sensitive and specific.”
The high-throughput sequencing in this study was performed using ImmunoSEQ, an assay developed by Adaptive Biotechnologies. The company did not sponsor the study, but company employees were involved in the research.
New research suggests DNA sequencing can reveal which patients with early stage mycosis fungoides (MF) will develop aggressive disease.
By sequencing the T-cell receptor beta gene (TCRB) in skin biopsies from MF patients, investigators were able to measure the tumor clone frequency (TCF), or the percentage of all T cells that represent the MF clone.
The researchers found the TCF could predict progression-free survival (PFS) and overall survival (OS).
In fact, for patients with early stage MF, TCF was a stronger predictor of PFS than other established prognostic factors.
“While more work needs to be done, we think this approach has the potential to prospectively identify a subgroup of patients who are destined to develop aggressive, life-threatening disease and treat them in a more aggressive fashion with the intent to better manage and, ideally, cure their cancer,” said Thomas Kupper, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“At the same time, we believe we can provide reassurance to patients with a low-risk (low TCF) profile that they are likely to survive indefinitely with conventional conservative therapies. As a physician who has treated this disease for decades, I am excited to be involved with work that so directly and profoundly affects the care and management of these patients.”
Dr Kupper and his colleagues described this work in Science Translational Medicine.
The researchers had previously published a study showing that high-throughput sequencing of the TCRB gene was an accurate way to diagnose cutaneous T-cell lymphoma (CTCL), including MF.
With the current study, the investigators set out to determine if the method could be used to predict progression and survival in patients with CTCL.
The team sequenced TCRB in lesional skin biopsies from 309 CTCL patients, most of whom had MF. The discovery cohort had 208 patients (177 with MF), and the validation cohort had 101 patients (87 with MF).
The sequencing produced a snapshot of the TCRB genes from a large number of cells at the site of the lesion. And the researchers could use this to measure TCF.
The team tested the association of TCF with prognosis in all CTCL patients in the discovery cohort and found a TCF greater than 25% in the skin was significantly associated with reduced PFS (P<0.001) and OS (P<0.001). Results were similar in the validation cohort (P<0.001 for PFS and OS).
The investigators also found that TCF was significantly associated with PFS (P<0.001) and OS (P<0.001) in MF patients but not in patients with Sézary syndrome. The team noted that they did not assess the predictive value of TCF in the blood of Sézary patients.
In a multivariable analysis, TCF was still significantly associated with PFS (P<0.001) and OS (P<0.001) in the MF patients.
The researchers also assessed potential prognostic variables in the early stage MF patients and found a TCF greater than 25% was a stronger predictor of PFS than any other established prognostic factor. This includes disease stage, presence of plaques, elevated lactate dehydrogenase, age, large-cell transformation, and CLIPI score.
“In reviewing the results, 2 different patients could have identical-looking skin lesions, but one might have a TCF of 8%, and one would have a TCF of 40%,” Dr Kupper noted. “The latter patient was highly likely to progress—something we would never have been able to predict before this discovery.”
“The TCF was independent of how thick or thin the skin lesions were. Most importantly, compared to all other currently used means of trying to predict which patients would progress, TCF was by far the most sensitive and specific.”
The high-throughput sequencing in this study was performed using ImmunoSEQ, an assay developed by Adaptive Biotechnologies. The company did not sponsor the study, but company employees were involved in the research.
Drug granted fast track designations for FL, DLBCL
The US Food and Drug Administration (FDA) has granted 2 fast track designations to 5F9, an anti-CD47 antibody.
The designations are for 5F9 as a treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).
Data supporting the fast track designations were derived from a phase 1b/2 trial of 5F9 in combination with rituximab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, including DLBCL and FL.
Forty Seven, Inc., the company developing 5F9, expects to announce initial safety and efficacy data from the phase 1b portion of the trial in the second quarter of 2018.
About fast track designation
The FDA’s fast track drug development program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers.
Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met.
Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.
The US Food and Drug Administration (FDA) has granted 2 fast track designations to 5F9, an anti-CD47 antibody.
The designations are for 5F9 as a treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).
Data supporting the fast track designations were derived from a phase 1b/2 trial of 5F9 in combination with rituximab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, including DLBCL and FL.
Forty Seven, Inc., the company developing 5F9, expects to announce initial safety and efficacy data from the phase 1b portion of the trial in the second quarter of 2018.
About fast track designation
The FDA’s fast track drug development program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers.
Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met.
Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.
The US Food and Drug Administration (FDA) has granted 2 fast track designations to 5F9, an anti-CD47 antibody.
The designations are for 5F9 as a treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).
Data supporting the fast track designations were derived from a phase 1b/2 trial of 5F9 in combination with rituximab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma, including DLBCL and FL.
Forty Seven, Inc., the company developing 5F9, expects to announce initial safety and efficacy data from the phase 1b portion of the trial in the second quarter of 2018.
About fast track designation
The FDA’s fast track drug development program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs.
Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers.
Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met.
Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.
FDA issues CRL for proposed biosimilar rituximab
The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) saying the agency cannot approve Sandoz’s proposed biosimilar rituximab.
Sandoz submitted the biologics licensing application for the product, known as GP2013, in September 2017.
The company was seeking approval for GP2013 to treat follicular lymphoma (FL), diffuse large B-cell lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.
The drug already has approval for these indications in Europe. The European Commission approved GP2013 (Rixathon) in June 2017.
As for US approval, Sandoz said it is evaluating the content of the FDA’s CRL and “remains committed to further discussions with FDA in order to bring this important medicine to US patients as soon as possible.”
The company said it “stands behind the robust body of evidence included in the regulatory submission” for GP2013.
Part of this evidence is the ASSIST-FL trial, in which researchers compared GP2013 to the reference product, Roche’s MabThera. Results from this trial were published in The Lancet Haematology and presented at ESMO 2017 Congress.
This phase 3 trial included adults with previously untreated, advanced stage FL. Patients received 8 cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.
At a median follow-up of 11.6 months, the overall response rate was 87% (271/311) in the GP2013 arm and 88% in the rituximab arm (274/313). Complete response rates were 15% (n=46) and 13% (n=42), respectively.
Rates of adverse events (AEs) were 93% in the GP2013 arm and 91% in the rituximab arm. Rates of serious AEs were 23% and 20%, respectively. The rate of discontinuation due to AEs was 7% in both arms.
The most common AE was neutropenia, which occurred in 26% of patients in the GP2013 arm and 30% of those in the rituximab arm in the combination phase. Rates of neutropenia in the maintenance phase were 10% and 6%, respectively.
The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) saying the agency cannot approve Sandoz’s proposed biosimilar rituximab.
Sandoz submitted the biologics licensing application for the product, known as GP2013, in September 2017.
The company was seeking approval for GP2013 to treat follicular lymphoma (FL), diffuse large B-cell lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.
The drug already has approval for these indications in Europe. The European Commission approved GP2013 (Rixathon) in June 2017.
As for US approval, Sandoz said it is evaluating the content of the FDA’s CRL and “remains committed to further discussions with FDA in order to bring this important medicine to US patients as soon as possible.”
The company said it “stands behind the robust body of evidence included in the regulatory submission” for GP2013.
Part of this evidence is the ASSIST-FL trial, in which researchers compared GP2013 to the reference product, Roche’s MabThera. Results from this trial were published in The Lancet Haematology and presented at ESMO 2017 Congress.
This phase 3 trial included adults with previously untreated, advanced stage FL. Patients received 8 cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.
At a median follow-up of 11.6 months, the overall response rate was 87% (271/311) in the GP2013 arm and 88% in the rituximab arm (274/313). Complete response rates were 15% (n=46) and 13% (n=42), respectively.
Rates of adverse events (AEs) were 93% in the GP2013 arm and 91% in the rituximab arm. Rates of serious AEs were 23% and 20%, respectively. The rate of discontinuation due to AEs was 7% in both arms.
The most common AE was neutropenia, which occurred in 26% of patients in the GP2013 arm and 30% of those in the rituximab arm in the combination phase. Rates of neutropenia in the maintenance phase were 10% and 6%, respectively.
The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) saying the agency cannot approve Sandoz’s proposed biosimilar rituximab.
Sandoz submitted the biologics licensing application for the product, known as GP2013, in September 2017.
The company was seeking approval for GP2013 to treat follicular lymphoma (FL), diffuse large B-cell lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.
The drug already has approval for these indications in Europe. The European Commission approved GP2013 (Rixathon) in June 2017.
As for US approval, Sandoz said it is evaluating the content of the FDA’s CRL and “remains committed to further discussions with FDA in order to bring this important medicine to US patients as soon as possible.”
The company said it “stands behind the robust body of evidence included in the regulatory submission” for GP2013.
Part of this evidence is the ASSIST-FL trial, in which researchers compared GP2013 to the reference product, Roche’s MabThera. Results from this trial were published in The Lancet Haematology and presented at ESMO 2017 Congress.
This phase 3 trial included adults with previously untreated, advanced stage FL. Patients received 8 cycles of cyclophosphamide, vincristine, and prednisone with either GP2013 or reference rituximab. Responders then received GP2013 or rituximab monotherapy as maintenance for up to 2 years.
At a median follow-up of 11.6 months, the overall response rate was 87% (271/311) in the GP2013 arm and 88% in the rituximab arm (274/313). Complete response rates were 15% (n=46) and 13% (n=42), respectively.
Rates of adverse events (AEs) were 93% in the GP2013 arm and 91% in the rituximab arm. Rates of serious AEs were 23% and 20%, respectively. The rate of discontinuation due to AEs was 7% in both arms.
The most common AE was neutropenia, which occurred in 26% of patients in the GP2013 arm and 30% of those in the rituximab arm in the combination phase. Rates of neutropenia in the maintenance phase were 10% and 6%, respectively.
FDA approves CAR T-cell therapy for lymphoma
The US Food and Drug Administration (FDA) has approved tisagenlecleucel (Kymriah®) for its second indication.
The chimeric antigen receptor (CAR) T-cell therapy is now approved to treat adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy.
This includes patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
The application for tisagenlecleucel in B-cell lymphoma was granted priority review. The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
Tisagenlecleucel is also FDA-approved to treat patients age 25 and younger who have B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.
Access to tisagenlecleucel
The prescribing information for tisagenlecleucel includes a boxed warning detailing the risk of cytokine release syndrome (CRS) and neurological toxicities for patients receiving tisagenlecleucel.
Because of these risks, tisagenlecleucel is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. The REMS program serves to inform and educate healthcare professionals about the risks associated with tisagenlecleucel treatment.
Novartis, the company marketing tisagenlecleucel, has established a network of certified treatment centers throughout the US. Staff at these centers are trained on the use of tisagenlecleucel and appropriate patient care.
Tisagenlecleucel is manufactured at a Novartis facility in Morris Plains, New Jersey. In the US, the target turnaround time for manufacturing tisagenlecleucel is 22 days.
Tisagenlecleucel costs $475,000 for a single course of treatment. However, Novartis said it is collaborating with the US Centers for Medicare and Medicaid Services on the creation of an appropriate value-based pricing approach.
The company also has a program called KYMRIAH CARES™, which offers financial assistance to eligible patients to help them gain access to tisagenlecleucel.
Phase 2 trial
The FDA approval of tisagenlecleucel for adults with relapsed/refractory B-cell lymphoma is based on results of the phase 2 JULIET trial.
The prescribing information for tisagenlecleucel includes data on 106 patients treated on this trial.
Only 68 of these patients were evaluable for efficacy. They had a median age of 56 (range, 22 to 74), and 71% were male.
Seventy-eight percent of patients had primary DLBCL not otherwise specified, and 22% had DLBCL following transformation from follicular lymphoma. Seventeen percent had high grade DLBCL.
Fifty-six percent of patients had refractory disease, and 44% had relapsed after their last therapy. The median number of prior therapies was 3 (range, 1 to 6), and 44% of patients had undergone autologous transplant.
Ninety percent of patients received lymphodepleting chemotherapy (66% fludarabine and 24% bendamustine) prior to tisagenlecleucel, and 10% did not. The median dose of tisagenlecleucel was 3.5 × 108 CAR+ T cells (range, 1.0 to 5.2 × 108).
The overall response rate was 50%, with 32% of patients achieving a complete response and 18% achieving a partial response. The median duration of response was not reached with a median follow-up of 9.4 months.
In all 106 patients infused with tisagenlecleucel, the most common grade 3/4 adverse events were infections (25%), CRS (23%), neurologic events (18%), febrile neutropenia (17%), encephalopathy (11%), lymphopenia (94%), neutropenia (81%), leukopenia (77%), anemia (58%), thrombocytopenia (54%), hypophosphatemia (24%), hypokalemia (12%), and hyponatremia (11%).
Three patients died within 30 days of tisagenlecleucel infusion. All of them had CRS and either stable or progressive disease. One of these patients developed bowel necrosis.
One patient died of infection. There were no deaths attributed to neurological events, and no fatal cases of cerebral edema.
The US Food and Drug Administration (FDA) has approved tisagenlecleucel (Kymriah®) for its second indication.
The chimeric antigen receptor (CAR) T-cell therapy is now approved to treat adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy.
This includes patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
The application for tisagenlecleucel in B-cell lymphoma was granted priority review. The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
Tisagenlecleucel is also FDA-approved to treat patients age 25 and younger who have B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.
Access to tisagenlecleucel
The prescribing information for tisagenlecleucel includes a boxed warning detailing the risk of cytokine release syndrome (CRS) and neurological toxicities for patients receiving tisagenlecleucel.
Because of these risks, tisagenlecleucel is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. The REMS program serves to inform and educate healthcare professionals about the risks associated with tisagenlecleucel treatment.
Novartis, the company marketing tisagenlecleucel, has established a network of certified treatment centers throughout the US. Staff at these centers are trained on the use of tisagenlecleucel and appropriate patient care.
Tisagenlecleucel is manufactured at a Novartis facility in Morris Plains, New Jersey. In the US, the target turnaround time for manufacturing tisagenlecleucel is 22 days.
Tisagenlecleucel costs $475,000 for a single course of treatment. However, Novartis said it is collaborating with the US Centers for Medicare and Medicaid Services on the creation of an appropriate value-based pricing approach.
The company also has a program called KYMRIAH CARES™, which offers financial assistance to eligible patients to help them gain access to tisagenlecleucel.
Phase 2 trial
The FDA approval of tisagenlecleucel for adults with relapsed/refractory B-cell lymphoma is based on results of the phase 2 JULIET trial.
The prescribing information for tisagenlecleucel includes data on 106 patients treated on this trial.
Only 68 of these patients were evaluable for efficacy. They had a median age of 56 (range, 22 to 74), and 71% were male.
Seventy-eight percent of patients had primary DLBCL not otherwise specified, and 22% had DLBCL following transformation from follicular lymphoma. Seventeen percent had high grade DLBCL.
Fifty-six percent of patients had refractory disease, and 44% had relapsed after their last therapy. The median number of prior therapies was 3 (range, 1 to 6), and 44% of patients had undergone autologous transplant.
Ninety percent of patients received lymphodepleting chemotherapy (66% fludarabine and 24% bendamustine) prior to tisagenlecleucel, and 10% did not. The median dose of tisagenlecleucel was 3.5 × 108 CAR+ T cells (range, 1.0 to 5.2 × 108).
The overall response rate was 50%, with 32% of patients achieving a complete response and 18% achieving a partial response. The median duration of response was not reached with a median follow-up of 9.4 months.
In all 106 patients infused with tisagenlecleucel, the most common grade 3/4 adverse events were infections (25%), CRS (23%), neurologic events (18%), febrile neutropenia (17%), encephalopathy (11%), lymphopenia (94%), neutropenia (81%), leukopenia (77%), anemia (58%), thrombocytopenia (54%), hypophosphatemia (24%), hypokalemia (12%), and hyponatremia (11%).
Three patients died within 30 days of tisagenlecleucel infusion. All of them had CRS and either stable or progressive disease. One of these patients developed bowel necrosis.
One patient died of infection. There were no deaths attributed to neurological events, and no fatal cases of cerebral edema.
The US Food and Drug Administration (FDA) has approved tisagenlecleucel (Kymriah®) for its second indication.
The chimeric antigen receptor (CAR) T-cell therapy is now approved to treat adults with relapsed or refractory large B-cell lymphoma after 2 or more lines of systemic therapy.
This includes patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma.
The application for tisagenlecleucel in B-cell lymphoma was granted priority review. The FDA aims to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.
Tisagenlecleucel is also FDA-approved to treat patients age 25 and younger who have B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.
Access to tisagenlecleucel
The prescribing information for tisagenlecleucel includes a boxed warning detailing the risk of cytokine release syndrome (CRS) and neurological toxicities for patients receiving tisagenlecleucel.
Because of these risks, tisagenlecleucel is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. The REMS program serves to inform and educate healthcare professionals about the risks associated with tisagenlecleucel treatment.
Novartis, the company marketing tisagenlecleucel, has established a network of certified treatment centers throughout the US. Staff at these centers are trained on the use of tisagenlecleucel and appropriate patient care.
Tisagenlecleucel is manufactured at a Novartis facility in Morris Plains, New Jersey. In the US, the target turnaround time for manufacturing tisagenlecleucel is 22 days.
Tisagenlecleucel costs $475,000 for a single course of treatment. However, Novartis said it is collaborating with the US Centers for Medicare and Medicaid Services on the creation of an appropriate value-based pricing approach.
The company also has a program called KYMRIAH CARES™, which offers financial assistance to eligible patients to help them gain access to tisagenlecleucel.
Phase 2 trial
The FDA approval of tisagenlecleucel for adults with relapsed/refractory B-cell lymphoma is based on results of the phase 2 JULIET trial.
The prescribing information for tisagenlecleucel includes data on 106 patients treated on this trial.
Only 68 of these patients were evaluable for efficacy. They had a median age of 56 (range, 22 to 74), and 71% were male.
Seventy-eight percent of patients had primary DLBCL not otherwise specified, and 22% had DLBCL following transformation from follicular lymphoma. Seventeen percent had high grade DLBCL.
Fifty-six percent of patients had refractory disease, and 44% had relapsed after their last therapy. The median number of prior therapies was 3 (range, 1 to 6), and 44% of patients had undergone autologous transplant.
Ninety percent of patients received lymphodepleting chemotherapy (66% fludarabine and 24% bendamustine) prior to tisagenlecleucel, and 10% did not. The median dose of tisagenlecleucel was 3.5 × 108 CAR+ T cells (range, 1.0 to 5.2 × 108).
The overall response rate was 50%, with 32% of patients achieving a complete response and 18% achieving a partial response. The median duration of response was not reached with a median follow-up of 9.4 months.
In all 106 patients infused with tisagenlecleucel, the most common grade 3/4 adverse events were infections (25%), CRS (23%), neurologic events (18%), febrile neutropenia (17%), encephalopathy (11%), lymphopenia (94%), neutropenia (81%), leukopenia (77%), anemia (58%), thrombocytopenia (54%), hypophosphatemia (24%), hypokalemia (12%), and hyponatremia (11%).
Three patients died within 30 days of tisagenlecleucel infusion. All of them had CRS and either stable or progressive disease. One of these patients developed bowel necrosis.
One patient died of infection. There were no deaths attributed to neurological events, and no fatal cases of cerebral edema.
Predicting response to CAR T-cell therapy in CLL
Researchers may have discovered why some patients with advanced chronic lymphocytic leukemia (CLL) don’t respond to chimeric antigen receptor (CAR) T-cell therapy.
The team found that CLL patients with elevated levels of “early memory” T cells prior to receiving CAR T-cell therapy had a partial or complete response to treatment, while patients with lower levels of these T cells did not respond.
The early memory T cells were marked by the expression of CD8 and CD27, as well as the absence of CD45RO.
The researchers validated the association between the early memory T cells and response in a small group of patients, predicting with 100% accuracy which patients would achieve a complete response.
Joseph A. Fraietta, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in Nature Medicine. This research was supported, in part, by Novartis.
For this study, the researchers retrospectively analyzed 41 patients with advanced, heavily pretreated, high-risk CLL who received at least 1 dose of CD19-directed CAR T cells.
Consistent with the team’s previously reported findings, they were not able to identify patient or disease-specific factors that predict who responds best to the therapy.
Therefore, the researchers compared the gene expression profiles and phenotypes of T cells in patients who had a complete response, partial response, or no response to therapy.
The CAR T cells that persisted and expanded in complete responders were enriched in genes that regulate early memory and effector T cells and possess the IL-6/STAT3 signature.
Non-responders, on the other hand, expressed genes involved in late T-cell differentiation, glycolysis, exhaustion, and apoptosis. These characteristics make for a weaker set of T cells to persist, expand, and fight the CLL.
“Pre-existing T-cell qualities have previously been associated with poor clinical response to cancer therapy, as well differentiation in the T cells,” Dr Fraietta said. “What is special about what we have done here is finding that critical cell subset and signature.”
Elevated levels of the IL-6/STAT3 signaling pathway in these early T cells correlated with clinical responses to CAR T-cell therapy.
To validate these findings, the researchers screened for the early memory T cells in a group of 8 CLL patients, before and after CAR T-cell therapy. The team identified the complete responders with 100% specificity and sensitivity.
“With a very robust biomarker like this, we can take a blood sample, measure the frequency of this T-cell population, and decide with a degree of confidence whether we can apply this therapy and know the patient would have a response,” Dr Fraietta said.
“The ability to select patients most likely to respond would have tremendous clinical impact, as this therapy would be applied only to patients most likely to benefit, allowing patients unlikely to respond to pursue other options.”
These findings also suggest the possibility of improving CAR T-cell therapy by selecting for cell manufacturing the subpopulation of T cells responsible for driving responses. However, this approach would come with challenges.
“What we’ve seen in these non-responders is that the frequency of these T cells is low, so it would be very hard to infuse them as starting populations,” said study author J. Joseph Melenhorst, PhD, also of the University of Pennsylvania.
“But one way to potentially boost their efficacy is by adding checkpoint inhibitors with the therapy to block the negative regulation prior to CAR T-cell therapy, which a past, separate study has shown can help elicit responses in these patients.”
The researchers also noted that it’s unclear why some patients’ T cells are suboptimal prior to treatment. However, the team believes this could have to do with prior therapies.
Future studies with a larger group of CLL patients should be conducted to help answer these questions and validate the findings from this study, the researchers said.
Researchers may have discovered why some patients with advanced chronic lymphocytic leukemia (CLL) don’t respond to chimeric antigen receptor (CAR) T-cell therapy.
The team found that CLL patients with elevated levels of “early memory” T cells prior to receiving CAR T-cell therapy had a partial or complete response to treatment, while patients with lower levels of these T cells did not respond.
The early memory T cells were marked by the expression of CD8 and CD27, as well as the absence of CD45RO.
The researchers validated the association between the early memory T cells and response in a small group of patients, predicting with 100% accuracy which patients would achieve a complete response.
Joseph A. Fraietta, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in Nature Medicine. This research was supported, in part, by Novartis.
For this study, the researchers retrospectively analyzed 41 patients with advanced, heavily pretreated, high-risk CLL who received at least 1 dose of CD19-directed CAR T cells.
Consistent with the team’s previously reported findings, they were not able to identify patient or disease-specific factors that predict who responds best to the therapy.
Therefore, the researchers compared the gene expression profiles and phenotypes of T cells in patients who had a complete response, partial response, or no response to therapy.
The CAR T cells that persisted and expanded in complete responders were enriched in genes that regulate early memory and effector T cells and possess the IL-6/STAT3 signature.
Non-responders, on the other hand, expressed genes involved in late T-cell differentiation, glycolysis, exhaustion, and apoptosis. These characteristics make for a weaker set of T cells to persist, expand, and fight the CLL.
“Pre-existing T-cell qualities have previously been associated with poor clinical response to cancer therapy, as well differentiation in the T cells,” Dr Fraietta said. “What is special about what we have done here is finding that critical cell subset and signature.”
Elevated levels of the IL-6/STAT3 signaling pathway in these early T cells correlated with clinical responses to CAR T-cell therapy.
To validate these findings, the researchers screened for the early memory T cells in a group of 8 CLL patients, before and after CAR T-cell therapy. The team identified the complete responders with 100% specificity and sensitivity.
“With a very robust biomarker like this, we can take a blood sample, measure the frequency of this T-cell population, and decide with a degree of confidence whether we can apply this therapy and know the patient would have a response,” Dr Fraietta said.
“The ability to select patients most likely to respond would have tremendous clinical impact, as this therapy would be applied only to patients most likely to benefit, allowing patients unlikely to respond to pursue other options.”
These findings also suggest the possibility of improving CAR T-cell therapy by selecting for cell manufacturing the subpopulation of T cells responsible for driving responses. However, this approach would come with challenges.
“What we’ve seen in these non-responders is that the frequency of these T cells is low, so it would be very hard to infuse them as starting populations,” said study author J. Joseph Melenhorst, PhD, also of the University of Pennsylvania.
“But one way to potentially boost their efficacy is by adding checkpoint inhibitors with the therapy to block the negative regulation prior to CAR T-cell therapy, which a past, separate study has shown can help elicit responses in these patients.”
The researchers also noted that it’s unclear why some patients’ T cells are suboptimal prior to treatment. However, the team believes this could have to do with prior therapies.
Future studies with a larger group of CLL patients should be conducted to help answer these questions and validate the findings from this study, the researchers said.
Researchers may have discovered why some patients with advanced chronic lymphocytic leukemia (CLL) don’t respond to chimeric antigen receptor (CAR) T-cell therapy.
The team found that CLL patients with elevated levels of “early memory” T cells prior to receiving CAR T-cell therapy had a partial or complete response to treatment, while patients with lower levels of these T cells did not respond.
The early memory T cells were marked by the expression of CD8 and CD27, as well as the absence of CD45RO.
The researchers validated the association between the early memory T cells and response in a small group of patients, predicting with 100% accuracy which patients would achieve a complete response.
Joseph A. Fraietta, PhD, of the University of Pennsylvania in Philadelphia, and his colleagues reported these findings in Nature Medicine. This research was supported, in part, by Novartis.
For this study, the researchers retrospectively analyzed 41 patients with advanced, heavily pretreated, high-risk CLL who received at least 1 dose of CD19-directed CAR T cells.
Consistent with the team’s previously reported findings, they were not able to identify patient or disease-specific factors that predict who responds best to the therapy.
Therefore, the researchers compared the gene expression profiles and phenotypes of T cells in patients who had a complete response, partial response, or no response to therapy.
The CAR T cells that persisted and expanded in complete responders were enriched in genes that regulate early memory and effector T cells and possess the IL-6/STAT3 signature.
Non-responders, on the other hand, expressed genes involved in late T-cell differentiation, glycolysis, exhaustion, and apoptosis. These characteristics make for a weaker set of T cells to persist, expand, and fight the CLL.
“Pre-existing T-cell qualities have previously been associated with poor clinical response to cancer therapy, as well differentiation in the T cells,” Dr Fraietta said. “What is special about what we have done here is finding that critical cell subset and signature.”
Elevated levels of the IL-6/STAT3 signaling pathway in these early T cells correlated with clinical responses to CAR T-cell therapy.
To validate these findings, the researchers screened for the early memory T cells in a group of 8 CLL patients, before and after CAR T-cell therapy. The team identified the complete responders with 100% specificity and sensitivity.
“With a very robust biomarker like this, we can take a blood sample, measure the frequency of this T-cell population, and decide with a degree of confidence whether we can apply this therapy and know the patient would have a response,” Dr Fraietta said.
“The ability to select patients most likely to respond would have tremendous clinical impact, as this therapy would be applied only to patients most likely to benefit, allowing patients unlikely to respond to pursue other options.”
These findings also suggest the possibility of improving CAR T-cell therapy by selecting for cell manufacturing the subpopulation of T cells responsible for driving responses. However, this approach would come with challenges.
“What we’ve seen in these non-responders is that the frequency of these T cells is low, so it would be very hard to infuse them as starting populations,” said study author J. Joseph Melenhorst, PhD, also of the University of Pennsylvania.
“But one way to potentially boost their efficacy is by adding checkpoint inhibitors with the therapy to block the negative regulation prior to CAR T-cell therapy, which a past, separate study has shown can help elicit responses in these patients.”
The researchers also noted that it’s unclear why some patients’ T cells are suboptimal prior to treatment. However, the team believes this could have to do with prior therapies.
Future studies with a larger group of CLL patients should be conducted to help answer these questions and validate the findings from this study, the researchers said.
Team identifies 5 subtypes of DLBCL
New research has revealed 5 genetic subtypes of diffuse large B-cell lymphoma (DLBCL).
Researchers identified a group of low-risk activated B-cell (ABC) DLBCLs, 2 subsets of germinal center B-cell (GCB) DLBCLs, a group of ABC/GCB-independent DLBCLs, and a group of ABC DLBCLs with genetic characteristics found in primary central nervous system lymphoma and testicular lymphoma.
The researchers believe these findings may have revealed new therapeutic targets for DLBCL, some of which could be inhibited by drugs that are already approved or under investigation in clinical trials.
Margaret Shipp, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Nature Medicine.
The team performed genetic analyses on samples from 304 DLBCL patients and observed great genetic diversity. The median number of genetic driver alterations in individual tumors was 17.
The researchers integrated data on 3 types of genetic alterations—recurrent mutations, somatic copy number alterations, and structural variants—to define previously unappreciated DLBCL subtypes.
“Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all 3 types of genetic alterations,” Dr Shipp noted.
“Most importantly, we saw that there were 5 discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.”
The researchers classified these subtypes as clusters (C) 1 to 5.
C1 consisted of largely ABC-DLBCLs with genetic features of an extra-follicular, possibly marginal zone origin.
C2 included both ABC and GCB DLBCLs with biallelic inactivation of TP53, 9p21.3/CDKN2A, and associated genomic instability.
Most DLBCLs in C3 were of the GCB subtype and were characterized by BCL2 structural variants and alterations of PTEN and epigenetic enzymes.
C4 consisted largely of GCB DLBCLs with alterations in BCR/PI3K, JAK/STAT, and BRAF pathway components and multiple histones.
Most C5 DLBCLs were of the ABC subtype, and the researchers said the major components of the C5 signature—BCL2 gain, concordant MYD88L265P/CD79B mutations, and mutations of ETV6, PIM1, GRHPR, TBL1XR1, and BTG1—were similar to those observed in primary central nervous system and testicular lymphoma.
Dr Shipp and her colleagues also identified a sixth cluster of DLBCLs (dubbed C0) that “lacked defining genetic drivers.”
Finally, the team found that patients with C0, C1, and C4 DLBCLs had more favorable outcomes, while patients with C2, C3, and C5 DLBCLs had less favorable outcomes.
“We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,” Dr Shipp said.
She and her colleagues are now working on creating a clinical tool to identify these genetic signatures in patients. The team is also developing clinical trials that will match patients with given genetic signatures to targeted treatments.
Another group of researchers recently identified 4 genetic subtypes of DLBCL.
New research has revealed 5 genetic subtypes of diffuse large B-cell lymphoma (DLBCL).
Researchers identified a group of low-risk activated B-cell (ABC) DLBCLs, 2 subsets of germinal center B-cell (GCB) DLBCLs, a group of ABC/GCB-independent DLBCLs, and a group of ABC DLBCLs with genetic characteristics found in primary central nervous system lymphoma and testicular lymphoma.
The researchers believe these findings may have revealed new therapeutic targets for DLBCL, some of which could be inhibited by drugs that are already approved or under investigation in clinical trials.
Margaret Shipp, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Nature Medicine.
The team performed genetic analyses on samples from 304 DLBCL patients and observed great genetic diversity. The median number of genetic driver alterations in individual tumors was 17.
The researchers integrated data on 3 types of genetic alterations—recurrent mutations, somatic copy number alterations, and structural variants—to define previously unappreciated DLBCL subtypes.
“Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all 3 types of genetic alterations,” Dr Shipp noted.
“Most importantly, we saw that there were 5 discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.”
The researchers classified these subtypes as clusters (C) 1 to 5.
C1 consisted of largely ABC-DLBCLs with genetic features of an extra-follicular, possibly marginal zone origin.
C2 included both ABC and GCB DLBCLs with biallelic inactivation of TP53, 9p21.3/CDKN2A, and associated genomic instability.
Most DLBCLs in C3 were of the GCB subtype and were characterized by BCL2 structural variants and alterations of PTEN and epigenetic enzymes.
C4 consisted largely of GCB DLBCLs with alterations in BCR/PI3K, JAK/STAT, and BRAF pathway components and multiple histones.
Most C5 DLBCLs were of the ABC subtype, and the researchers said the major components of the C5 signature—BCL2 gain, concordant MYD88L265P/CD79B mutations, and mutations of ETV6, PIM1, GRHPR, TBL1XR1, and BTG1—were similar to those observed in primary central nervous system and testicular lymphoma.
Dr Shipp and her colleagues also identified a sixth cluster of DLBCLs (dubbed C0) that “lacked defining genetic drivers.”
Finally, the team found that patients with C0, C1, and C4 DLBCLs had more favorable outcomes, while patients with C2, C3, and C5 DLBCLs had less favorable outcomes.
“We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,” Dr Shipp said.
She and her colleagues are now working on creating a clinical tool to identify these genetic signatures in patients. The team is also developing clinical trials that will match patients with given genetic signatures to targeted treatments.
Another group of researchers recently identified 4 genetic subtypes of DLBCL.
New research has revealed 5 genetic subtypes of diffuse large B-cell lymphoma (DLBCL).
Researchers identified a group of low-risk activated B-cell (ABC) DLBCLs, 2 subsets of germinal center B-cell (GCB) DLBCLs, a group of ABC/GCB-independent DLBCLs, and a group of ABC DLBCLs with genetic characteristics found in primary central nervous system lymphoma and testicular lymphoma.
The researchers believe these findings may have revealed new therapeutic targets for DLBCL, some of which could be inhibited by drugs that are already approved or under investigation in clinical trials.
Margaret Shipp, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and her colleagues conducted this research and reported the results in Nature Medicine.
The team performed genetic analyses on samples from 304 DLBCL patients and observed great genetic diversity. The median number of genetic driver alterations in individual tumors was 17.
The researchers integrated data on 3 types of genetic alterations—recurrent mutations, somatic copy number alterations, and structural variants—to define previously unappreciated DLBCL subtypes.
“Specific genes that were perturbed by mutations could also be altered by changes in gene copy numbers or by chromosomal rearrangements, underscoring the importance of evaluating all 3 types of genetic alterations,” Dr Shipp noted.
“Most importantly, we saw that there were 5 discrete types of DLBCL that were distinguished one from another on the basis of the specific types of genetic alterations that occurred in combination.”
The researchers classified these subtypes as clusters (C) 1 to 5.
C1 consisted of largely ABC-DLBCLs with genetic features of an extra-follicular, possibly marginal zone origin.
C2 included both ABC and GCB DLBCLs with biallelic inactivation of TP53, 9p21.3/CDKN2A, and associated genomic instability.
Most DLBCLs in C3 were of the GCB subtype and were characterized by BCL2 structural variants and alterations of PTEN and epigenetic enzymes.
C4 consisted largely of GCB DLBCLs with alterations in BCR/PI3K, JAK/STAT, and BRAF pathway components and multiple histones.
Most C5 DLBCLs were of the ABC subtype, and the researchers said the major components of the C5 signature—BCL2 gain, concordant MYD88L265P/CD79B mutations, and mutations of ETV6, PIM1, GRHPR, TBL1XR1, and BTG1—were similar to those observed in primary central nervous system and testicular lymphoma.
Dr Shipp and her colleagues also identified a sixth cluster of DLBCLs (dubbed C0) that “lacked defining genetic drivers.”
Finally, the team found that patients with C0, C1, and C4 DLBCLs had more favorable outcomes, while patients with C2, C3, and C5 DLBCLs had less favorable outcomes.
“We feel this research opens the door to a whole series of additional investigations to understand how the combinations of these genetic alterations work together, and then to use that information to benefit patients with targeted therapies,” Dr Shipp said.
She and her colleagues are now working on creating a clinical tool to identify these genetic signatures in patients. The team is also developing clinical trials that will match patients with given genetic signatures to targeted treatments.
Another group of researchers recently identified 4 genetic subtypes of DLBCL.
CHMP recommends approval for generic carmustine
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of Carmustine Obvius, a generic version of Carmubris.
The CHMP is recommending marketing authorization for Carmustine Obvius as second-line treatment for Hodgkin and non-Hodgkin lymphoma as well as to treat new or recurrent brain tumors, including glioblastoma, medulloblastoma, astrocytoma, and metastatic brain tumors.
The CHMP’s opinion on Carmustine Obvius will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP’s recommendation, the commission will grant a centralized marketing authorization that will be valid in the European Union.
The EC typically makes a decision on a product within 67 days of the CHMP’s recommendation.
If approved, Carmustine Obvius will be available as a 100 mg powder and solvent for solution for infusion.
The active substance of Carmustine Obvius is carmustine, an alkylating antineoplastic agent of the nitrosourea type, which prevents DNA replication and transcription by alkylating reactive sites on nucleoproteins.
Carmustine Obvius is a generic of Carmubris, which has been authorized in the European Union since July 31, 1996.
Since Carmustine Obvius is administered intravenously and is 100% bioavailable, a bioequivalence study of the drug versus Carmubris was not required.
Carmustine Obvius is a product of Obvius Investment B.V.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of Carmustine Obvius, a generic version of Carmubris.
The CHMP is recommending marketing authorization for Carmustine Obvius as second-line treatment for Hodgkin and non-Hodgkin lymphoma as well as to treat new or recurrent brain tumors, including glioblastoma, medulloblastoma, astrocytoma, and metastatic brain tumors.
The CHMP’s opinion on Carmustine Obvius will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP’s recommendation, the commission will grant a centralized marketing authorization that will be valid in the European Union.
The EC typically makes a decision on a product within 67 days of the CHMP’s recommendation.
If approved, Carmustine Obvius will be available as a 100 mg powder and solvent for solution for infusion.
The active substance of Carmustine Obvius is carmustine, an alkylating antineoplastic agent of the nitrosourea type, which prevents DNA replication and transcription by alkylating reactive sites on nucleoproteins.
Carmustine Obvius is a generic of Carmubris, which has been authorized in the European Union since July 31, 1996.
Since Carmustine Obvius is administered intravenously and is 100% bioavailable, a bioequivalence study of the drug versus Carmubris was not required.
Carmustine Obvius is a product of Obvius Investment B.V.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion of Carmustine Obvius, a generic version of Carmubris.
The CHMP is recommending marketing authorization for Carmustine Obvius as second-line treatment for Hodgkin and non-Hodgkin lymphoma as well as to treat new or recurrent brain tumors, including glioblastoma, medulloblastoma, astrocytoma, and metastatic brain tumors.
The CHMP’s opinion on Carmustine Obvius will be reviewed by the European Commission (EC).
If the EC agrees with the CHMP’s recommendation, the commission will grant a centralized marketing authorization that will be valid in the European Union.
The EC typically makes a decision on a product within 67 days of the CHMP’s recommendation.
If approved, Carmustine Obvius will be available as a 100 mg powder and solvent for solution for infusion.
The active substance of Carmustine Obvius is carmustine, an alkylating antineoplastic agent of the nitrosourea type, which prevents DNA replication and transcription by alkylating reactive sites on nucleoproteins.
Carmustine Obvius is a generic of Carmubris, which has been authorized in the European Union since July 31, 1996.
Since Carmustine Obvius is administered intravenously and is 100% bioavailable, a bioequivalence study of the drug versus Carmubris was not required.
Carmustine Obvius is a product of Obvius Investment B.V.