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CAR T-cell therapy bb2121 performs well in phase 1 trial of refractory multiple myeloma
Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.
The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.
The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.
The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.
After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.
All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.
The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.
SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.
Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.
The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.
The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.
The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.
After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.
All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.
The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.
SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.
Chimeric antigen receptor (CAR) T-cell therapy bb2121, which targets B-cell maturation agent (BCMA), appears safe and effective for treating patients with refractory multiple myeloma, according to results of a phase 1 trial.
The objective response rate of 85% among 33 heavily pretreated patients suggests “promising efficacy,” reported lead author Noopur Raje, MD, of Massachusetts General Hospital Cancer Center in Boston and colleagues.
“Although comparisons among studies are complicated by differences in patient populations, CAR constructs, administered doses, and grading scales of toxic effects, the results observed with bb2121 indicate a favorable safety profile,” the investigators wrote in a study published in the New England Journal of Medicine.
The study initially involved 36 patients with refractory multiple myeloma who had received at least three lines of prior therapy, including an immunomodulatory agent and a proteasome inhibitor. Although leukapheresis and therapy manufacturing were successful in all patients, three patients were excluded from receiving the infusion because of disease progression.
The 33 remaining patients were lymphodepleted with fludarabine and cyclophosphamide. Bridging therapy was allowed during the manufacturing process but was stopped at least 2 weeks prior to infusion. In the dose-escalation phase of the study, b2121 was delivered as a single infusion at one of four dose levels: 50 × 106, 150 × 106, 450 × 106, or 800 × 106 CAR T cells. In the expansion phase, the treatment was given at either 150 x 106 or 450 x 106 CAR T cells. The primary endpoint was safety; the secondary endpoints were response rate and duration of response.
After a median follow-up of 11.3 months, most patients (85%) had responded to therapy, and almost half (45%) had achieved a complete response. Of the 15 complete responders, 6 relapsed. The median progression-free survival was 11.8 months; stated differently, two out of five patients (40%) had not experienced disease progression after 1 year. CAR T cells were detectable 1 month after infusion in 96% of patients; however, this value dropped to 86% at 3 months, 57% at 6 months, and 20% at 12 months. The investigators noted that CAR T-cell persistence was associated with treatment response.
All patients had adverse events. Most (85%) had grade 3 or higher hematologic toxicity, which the investigators considered to be the “expected toxic effects of lymphodepleting chemotherapy.” Although other adverse events occurred in the majority of patients, these were generally mild to moderate. Cytokine release syndrome occurred in 25 patients (76%), including two instances of grade 3 toxicity but none of grade 4 or higher. Fourteen patients (42%) developed neurologic toxicities: Most were grade 1 or 2, but one patient had a grade 4 toxicity that resolved after a month. Infections occurred at the same rate (42%), although, again, most were grade 1 or 2.
The study was funded by Bluebird Bio and Celgene. The investigators disclosed financial relationships with Bluebird and other drug companies.
SOURCE: Raje N et al. NEJM. 1 May 2019. doi: 10.1056/NEJMoa1817226.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Advances in CAR T-Cell Therapies (FULL)
Gene therapies, especially chimeric antigen receptor (CAR) T-cell therapies, experienced significant growth in 2017. The CAR T-cell therapies are among the most clinically important of the adoptive cell transfer therapies. In August, the FDA approved tisagenlecleucel for patients aged < 26 years with acute or relapsed lymphoblastic leukemia (ALL). In October, the FDA approved axicabtagene ciloleucel for treatment of adult patients nonresponsive to, or relapsed from treatment of, certain types of large B-cell lymphoma. And in November, the FDA granted breakthrough therapy designation to Celgene and Bluebird Bio for the bb2121 anti-B-cell maturation antigen (BCMA) CAR T-cell therapy for relapsed and refractory multiple myeloma (MM).
Chimeric antigen receptor T-cells circumvent the human major histocompatibility complex that T-cell receptors must navigate, shifting cell-based therapy away from identification of existing cells and toward creating T-cell products through genetic engineering. This broadens the potential for CAR T-cell applications and allows for rapid manufacture of tumor and patient-specific agents.1 Both Novartis’ Kymriah and Kite Pharma’s Yescarta are derived from investigations into anti-CD19 CAR therapy, which has been the most heavily researched of the CARs due to its links with B-cell malignancies, expression in most tumor cells, and absence from vital tissues.2 Studied in relation to a number of cancers, CD19 has not shown much success in either MM or solid tumor cancers.
Targeting the right antigen for myeloma is complicated: first because common MM antigens—CD38, CD56, CD138—also are expressed on essential normal cells, and second, because myeloma cells are synonymous with heterogeneity. The FDA based its designation of bb2121, or BCMA CAR T-cell therapy, on preliminary data from an ongoing phase 1 CRB-401 trial that, as of December 2017, concluded that 94% of 21 patients with MM treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.3 The trial also showed that cytokine-release toxicity (CRS), although severe in some patients, was generally reversible and short lived.
Multiple myeloma BCMA is only one of several CAR targets under consideration for MM treatment; others include CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain. However, B-cell maturation antigen is attractive to researchers because BCMA–specific CAR-expressing T lymphocytes recognize and kill B-cell maturation antigen–expressing tumor cells. Also, BCMA acts as a receptor for both a proliferation-inducing ligand and as a B-cell–activating factor and is a member of the tumor necrosis factor receptor superfamily, playing a key role in plasma cell survival. B-cell maturation antigen is expressed in most, if not all, myeloma cells but not in epithelial tissues. Finally, integration of CAR-Ts with other myeloma therapies is an important area of future research.4
Most of the 23 trials looking at CAR T-cell therapy for MM are in the U.S. or China, and several deal jointly with MM, leukemia, and lymphoma. The THINK (THerapeutic Immunotherapy with NKR-2) multinational open-label phase 1 study stands alone in assessing the safety and clinical activity of multiple administrations of autologous NKR-2 cells in 7 refractory cancers, including 5 solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and 2 hematologic tumors (acute myeloid leukemia and MM). Unlike traditional CAR T-cell therapy, which targets only 1 tumor antigen, NK cell receptors enable a single receptor to recognize multiple tumor antigens.
Despite challenges of toxicity, costs, and restricted availability for immunotherapies, CAR T-cell therapies seem to offer great possibilities of groundbreaking treatments and possible cures for formerly hard to treat cancers, including MM.5
Click here to read the digital edition.
1. Almåsbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602.
2. Sadelain M. CAR therapy: the CD19 paradigm. J Clin Invest. 2015;125(9):3392-3400.
3. C
4. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130(24):2594-2602.
5. Vallet S, Pecherstorfer M, Podar K. Adoptive cell therapy in multiple myeloma. Expert Opin Biol Ther. 2017;17(12):1511-1522.
Gene therapies, especially chimeric antigen receptor (CAR) T-cell therapies, experienced significant growth in 2017. The CAR T-cell therapies are among the most clinically important of the adoptive cell transfer therapies. In August, the FDA approved tisagenlecleucel for patients aged < 26 years with acute or relapsed lymphoblastic leukemia (ALL). In October, the FDA approved axicabtagene ciloleucel for treatment of adult patients nonresponsive to, or relapsed from treatment of, certain types of large B-cell lymphoma. And in November, the FDA granted breakthrough therapy designation to Celgene and Bluebird Bio for the bb2121 anti-B-cell maturation antigen (BCMA) CAR T-cell therapy for relapsed and refractory multiple myeloma (MM).
Chimeric antigen receptor T-cells circumvent the human major histocompatibility complex that T-cell receptors must navigate, shifting cell-based therapy away from identification of existing cells and toward creating T-cell products through genetic engineering. This broadens the potential for CAR T-cell applications and allows for rapid manufacture of tumor and patient-specific agents.1 Both Novartis’ Kymriah and Kite Pharma’s Yescarta are derived from investigations into anti-CD19 CAR therapy, which has been the most heavily researched of the CARs due to its links with B-cell malignancies, expression in most tumor cells, and absence from vital tissues.2 Studied in relation to a number of cancers, CD19 has not shown much success in either MM or solid tumor cancers.
Targeting the right antigen for myeloma is complicated: first because common MM antigens—CD38, CD56, CD138—also are expressed on essential normal cells, and second, because myeloma cells are synonymous with heterogeneity. The FDA based its designation of bb2121, or BCMA CAR T-cell therapy, on preliminary data from an ongoing phase 1 CRB-401 trial that, as of December 2017, concluded that 94% of 21 patients with MM treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.3 The trial also showed that cytokine-release toxicity (CRS), although severe in some patients, was generally reversible and short lived.
Multiple myeloma BCMA is only one of several CAR targets under consideration for MM treatment; others include CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain. However, B-cell maturation antigen is attractive to researchers because BCMA–specific CAR-expressing T lymphocytes recognize and kill B-cell maturation antigen–expressing tumor cells. Also, BCMA acts as a receptor for both a proliferation-inducing ligand and as a B-cell–activating factor and is a member of the tumor necrosis factor receptor superfamily, playing a key role in plasma cell survival. B-cell maturation antigen is expressed in most, if not all, myeloma cells but not in epithelial tissues. Finally, integration of CAR-Ts with other myeloma therapies is an important area of future research.4
Most of the 23 trials looking at CAR T-cell therapy for MM are in the U.S. or China, and several deal jointly with MM, leukemia, and lymphoma. The THINK (THerapeutic Immunotherapy with NKR-2) multinational open-label phase 1 study stands alone in assessing the safety and clinical activity of multiple administrations of autologous NKR-2 cells in 7 refractory cancers, including 5 solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and 2 hematologic tumors (acute myeloid leukemia and MM). Unlike traditional CAR T-cell therapy, which targets only 1 tumor antigen, NK cell receptors enable a single receptor to recognize multiple tumor antigens.
Despite challenges of toxicity, costs, and restricted availability for immunotherapies, CAR T-cell therapies seem to offer great possibilities of groundbreaking treatments and possible cures for formerly hard to treat cancers, including MM.5
Click here to read the digital edition.
Gene therapies, especially chimeric antigen receptor (CAR) T-cell therapies, experienced significant growth in 2017. The CAR T-cell therapies are among the most clinically important of the adoptive cell transfer therapies. In August, the FDA approved tisagenlecleucel for patients aged < 26 years with acute or relapsed lymphoblastic leukemia (ALL). In October, the FDA approved axicabtagene ciloleucel for treatment of adult patients nonresponsive to, or relapsed from treatment of, certain types of large B-cell lymphoma. And in November, the FDA granted breakthrough therapy designation to Celgene and Bluebird Bio for the bb2121 anti-B-cell maturation antigen (BCMA) CAR T-cell therapy for relapsed and refractory multiple myeloma (MM).
Chimeric antigen receptor T-cells circumvent the human major histocompatibility complex that T-cell receptors must navigate, shifting cell-based therapy away from identification of existing cells and toward creating T-cell products through genetic engineering. This broadens the potential for CAR T-cell applications and allows for rapid manufacture of tumor and patient-specific agents.1 Both Novartis’ Kymriah and Kite Pharma’s Yescarta are derived from investigations into anti-CD19 CAR therapy, which has been the most heavily researched of the CARs due to its links with B-cell malignancies, expression in most tumor cells, and absence from vital tissues.2 Studied in relation to a number of cancers, CD19 has not shown much success in either MM or solid tumor cancers.
Targeting the right antigen for myeloma is complicated: first because common MM antigens—CD38, CD56, CD138—also are expressed on essential normal cells, and second, because myeloma cells are synonymous with heterogeneity. The FDA based its designation of bb2121, or BCMA CAR T-cell therapy, on preliminary data from an ongoing phase 1 CRB-401 trial that, as of December 2017, concluded that 94% of 21 patients with MM treated with the highest doses showed complete or partial remissions and high rates of progression-free survival.3 The trial also showed that cytokine-release toxicity (CRS), although severe in some patients, was generally reversible and short lived.
Multiple myeloma BCMA is only one of several CAR targets under consideration for MM treatment; others include CD138, CD38, signaling lymphocyte-activating molecule 7, and κ light chain. However, B-cell maturation antigen is attractive to researchers because BCMA–specific CAR-expressing T lymphocytes recognize and kill B-cell maturation antigen–expressing tumor cells. Also, BCMA acts as a receptor for both a proliferation-inducing ligand and as a B-cell–activating factor and is a member of the tumor necrosis factor receptor superfamily, playing a key role in plasma cell survival. B-cell maturation antigen is expressed in most, if not all, myeloma cells but not in epithelial tissues. Finally, integration of CAR-Ts with other myeloma therapies is an important area of future research.4
Most of the 23 trials looking at CAR T-cell therapy for MM are in the U.S. or China, and several deal jointly with MM, leukemia, and lymphoma. The THINK (THerapeutic Immunotherapy with NKR-2) multinational open-label phase 1 study stands alone in assessing the safety and clinical activity of multiple administrations of autologous NKR-2 cells in 7 refractory cancers, including 5 solid tumors (colorectal, ovarian, bladder, triple-negative breast and pancreatic cancers) and 2 hematologic tumors (acute myeloid leukemia and MM). Unlike traditional CAR T-cell therapy, which targets only 1 tumor antigen, NK cell receptors enable a single receptor to recognize multiple tumor antigens.
Despite challenges of toxicity, costs, and restricted availability for immunotherapies, CAR T-cell therapies seem to offer great possibilities of groundbreaking treatments and possible cures for formerly hard to treat cancers, including MM.5
Click here to read the digital edition.
1. Almåsbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602.
2. Sadelain M. CAR therapy: the CD19 paradigm. J Clin Invest. 2015;125(9):3392-3400.
3. C
4. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130(24):2594-2602.
5. Vallet S, Pecherstorfer M, Podar K. Adoptive cell therapy in multiple myeloma. Expert Opin Biol Ther. 2017;17(12):1511-1522.
1. Almåsbak H, Aarvak T, Vemuri MC. CAR T cell therapy: a game changer in cancer treatment. J Immunol Res. 2016;2016:5474602.
2. Sadelain M. CAR therapy: the CD19 paradigm. J Clin Invest. 2015;125(9):3392-3400.
3. C
4. Mikkilineni L, Kochenderfer JN. Chimeric antigen receptor T-cell therapies for multiple myeloma. Blood. 2017;130(24):2594-2602.
5. Vallet S, Pecherstorfer M, Podar K. Adoptive cell therapy in multiple myeloma. Expert Opin Biol Ther. 2017;17(12):1511-1522.
Obinutuzumab-based regimens yield durable remissions in CLL
Two different obinutuzumab-based chemoimmunotherapy regimens resulted in excellent long-term disease control as front-line therapy for chronic lymphocytic leukemia (CLL), investigators said in a follow-up report on a phase 1b study.
Both obinutuzumab plus fludarabine/cyclophosphamide (G-FC) and obinutuzumab plus bendamustine (G-B) were well tolerated, with adverse events similar to what has been reported in rituximab-containing immunotherapy regimens, they said in the report of final results from the GALTON trial.
Most evaluable patients had B-cell recovery by 36 months in the study, which included a population of CLL patients largely without 17p deletions, said Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, Boston, and her coinvestigators.
“These data support moving forward with these regimens in subsequent trials, which are currently ongoing,” they said in their report on the study, which appears in Blood.
The open-label, parallel-arm, multicenter phase 1b GALTON study included 41 patients with CLL, of whom 21 received G-FC and 20 received G-B for up to six cycles of 28 days each. The median age was 60 years, and about one-third of patients had Rai stage III or IV disease. Only one patient had del(17p), and nearly half of patients tested (17 of 38 patients) had unmutated immunoglobulin heavy-chain variable region gene (IGHV). Six patients had del(11q), including four in the G-FC arm and two in the G-B arm.
Both G-FC and G-B had manageable toxicities, with infusion-related reactions being the most common adverse event, occurring in 88% (20% grade 3 or 4), Dr. Brown and her colleagues reported, adding that grade 3 or 4 neutropenia was seen in 48% of the G-FC arm and 55% of the G-B arm.
The objective response rate (ORR) was 62% for G-FC and 90% for GB.
“The ORR in the G-FC arm likely does not reflect the true activity of the regimen, as it is based on an intent-to-treat analysis,” the investigators said.
With a median observation time of 40.4 months, 95% of patients were alive, and 90% had not experienced a progression-free survival event.
Nine patients in the G-FC arm underwent minimal residual disease (MRD) testing in peripheral blood; 100% had undetectable MRD, according to the report.
“With the caveat of small patient numbers and inevitable differences in patient populations across studies, these results suggest that G-FC may clear residual disease more effectively than rituximab plus FC,” the investigators wrote.
Previous studies of R-FC showed an undetectable MRD rate of 45% or less, they said.
The study was sponsored by Genentech. The investigators reported disclosures related to Genentech/Roche and other companies.
SOURCE: Brown JR et al. Blood. 2018 Dec 28. doi: 10.1182/blood-2018-06-857714.
Two different obinutuzumab-based chemoimmunotherapy regimens resulted in excellent long-term disease control as front-line therapy for chronic lymphocytic leukemia (CLL), investigators said in a follow-up report on a phase 1b study.
Both obinutuzumab plus fludarabine/cyclophosphamide (G-FC) and obinutuzumab plus bendamustine (G-B) were well tolerated, with adverse events similar to what has been reported in rituximab-containing immunotherapy regimens, they said in the report of final results from the GALTON trial.
Most evaluable patients had B-cell recovery by 36 months in the study, which included a population of CLL patients largely without 17p deletions, said Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, Boston, and her coinvestigators.
“These data support moving forward with these regimens in subsequent trials, which are currently ongoing,” they said in their report on the study, which appears in Blood.
The open-label, parallel-arm, multicenter phase 1b GALTON study included 41 patients with CLL, of whom 21 received G-FC and 20 received G-B for up to six cycles of 28 days each. The median age was 60 years, and about one-third of patients had Rai stage III or IV disease. Only one patient had del(17p), and nearly half of patients tested (17 of 38 patients) had unmutated immunoglobulin heavy-chain variable region gene (IGHV). Six patients had del(11q), including four in the G-FC arm and two in the G-B arm.
Both G-FC and G-B had manageable toxicities, with infusion-related reactions being the most common adverse event, occurring in 88% (20% grade 3 or 4), Dr. Brown and her colleagues reported, adding that grade 3 or 4 neutropenia was seen in 48% of the G-FC arm and 55% of the G-B arm.
The objective response rate (ORR) was 62% for G-FC and 90% for GB.
“The ORR in the G-FC arm likely does not reflect the true activity of the regimen, as it is based on an intent-to-treat analysis,” the investigators said.
With a median observation time of 40.4 months, 95% of patients were alive, and 90% had not experienced a progression-free survival event.
Nine patients in the G-FC arm underwent minimal residual disease (MRD) testing in peripheral blood; 100% had undetectable MRD, according to the report.
“With the caveat of small patient numbers and inevitable differences in patient populations across studies, these results suggest that G-FC may clear residual disease more effectively than rituximab plus FC,” the investigators wrote.
Previous studies of R-FC showed an undetectable MRD rate of 45% or less, they said.
The study was sponsored by Genentech. The investigators reported disclosures related to Genentech/Roche and other companies.
SOURCE: Brown JR et al. Blood. 2018 Dec 28. doi: 10.1182/blood-2018-06-857714.
Two different obinutuzumab-based chemoimmunotherapy regimens resulted in excellent long-term disease control as front-line therapy for chronic lymphocytic leukemia (CLL), investigators said in a follow-up report on a phase 1b study.
Both obinutuzumab plus fludarabine/cyclophosphamide (G-FC) and obinutuzumab plus bendamustine (G-B) were well tolerated, with adverse events similar to what has been reported in rituximab-containing immunotherapy regimens, they said in the report of final results from the GALTON trial.
Most evaluable patients had B-cell recovery by 36 months in the study, which included a population of CLL patients largely without 17p deletions, said Jennifer R. Brown, MD, PhD, of Dana-Farber Cancer Institute, Boston, and her coinvestigators.
“These data support moving forward with these regimens in subsequent trials, which are currently ongoing,” they said in their report on the study, which appears in Blood.
The open-label, parallel-arm, multicenter phase 1b GALTON study included 41 patients with CLL, of whom 21 received G-FC and 20 received G-B for up to six cycles of 28 days each. The median age was 60 years, and about one-third of patients had Rai stage III or IV disease. Only one patient had del(17p), and nearly half of patients tested (17 of 38 patients) had unmutated immunoglobulin heavy-chain variable region gene (IGHV). Six patients had del(11q), including four in the G-FC arm and two in the G-B arm.
Both G-FC and G-B had manageable toxicities, with infusion-related reactions being the most common adverse event, occurring in 88% (20% grade 3 or 4), Dr. Brown and her colleagues reported, adding that grade 3 or 4 neutropenia was seen in 48% of the G-FC arm and 55% of the G-B arm.
The objective response rate (ORR) was 62% for G-FC and 90% for GB.
“The ORR in the G-FC arm likely does not reflect the true activity of the regimen, as it is based on an intent-to-treat analysis,” the investigators said.
With a median observation time of 40.4 months, 95% of patients were alive, and 90% had not experienced a progression-free survival event.
Nine patients in the G-FC arm underwent minimal residual disease (MRD) testing in peripheral blood; 100% had undetectable MRD, according to the report.
“With the caveat of small patient numbers and inevitable differences in patient populations across studies, these results suggest that G-FC may clear residual disease more effectively than rituximab plus FC,” the investigators wrote.
Previous studies of R-FC showed an undetectable MRD rate of 45% or less, they said.
The study was sponsored by Genentech. The investigators reported disclosures related to Genentech/Roche and other companies.
SOURCE: Brown JR et al. Blood. 2018 Dec 28. doi: 10.1182/blood-2018-06-857714.
FROM BLOOD
Key clinical point:
Major finding: With a median observation time of 40.4 months, 95% of patients were alive, and 90% had not experienced a progression-free survival event.
Study details: Long-term follow-up of the phase 1b GALTON trial, including 41 patients with CLL.
Disclosures: The study was sponsored by Genentech. The study authors reported disclosures related to Genentech/Roche and other companies.
Source: Brown JR et al. Blood. 2018 Dec 28. doi: 10.1182/blood-2018-06-857714.
10 Important VA Studies You Might Have Missed at ASH
With hundreds of sessions and thousands of abstracts, it can be difficult to wade through all the new findings to find the most significant and relevant findings. Federal Practitioner consulted with Association of VA Hematology/Oncology members who attended the meeting, VA researchers, and other sources to provide these nuggets you might have missed on lymphomas, white blood cells, leukemias, and multiple myeloma:
Lymphomas
This retrospective analysis of diffuse large B cell lymphoma (DCBL) patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the VA Audie Murphy Hospital in San Antonio, Texas was compared with patients with DLBCL who received R-CHOP in a community setting. According to the researchers, the response to initial treatment was inferior in the veteran population when compared with a patient population with similar demographics and having similar time from diagnosis to treatment. Veteran patients also had worse outcomes when compared with uninsured patients.
This retrospective analysis study identified 2,290 patients with follicular lymphoma treated in the Veterans Health Administration between 2006–2014 and detailed their staging, demographics, and comorbidities. The researchers found that maintenance therapy with rituximab was associated with an improvement in overall survival.
Another retrospective analysis of DBCL using VHA data examined the effectiveness of second-line chemotherapy and chemoimmunotherapy in patients aged ≥ 65 years. The researchers found 230 patients from 2001 to 2015 that met the inclusion criteria. According to the researchers, the overall survival was < 1 year and about half of the patients "did not receive or were not candidates for regimens typically used with intent for high-dose therapy and autologous transplant."
White Blood Cells
Cost-Effective Use of White Blood Cell Growth Factors in the Veterans Administration
This study analyzed the use of granulocyte colony-stimulating (G-CSF) vs pegfilgrastim in the UD Department of Veterans Affairs (VA) health care system. The researchers looked at the relative frequency of use of filgrastim, Tbo-filgrastim, Filgrastim-sndz and pegfilgrastim at 23 VA sites and found that uptake of biosimilar G-CSF has been extremely rapid. All sites are using biosimilar GCSF for all new patients; 6 of 23 sites were comfortable shifting current patients on branded G-CSF to the biosimilar.However, switching to a Tbo-filgrastim brought a cost savings of 2.2% that was "small compared to other clinical changes."
This analysis described the association between white blood cell (EBC) levels and occurrence of thrombotic events among patients with polycythemia vera (PV) using Veterans Health Administration claims data collected between 2005 and 2012. The researchers found A significant, positive association between increased WBC counts and occurrence of thrombotic events in patients with PV was observed in this study. Patients with WBC counts ≥ 8.5 × 109/L had a significantly increased risk of thrombotic events, and those with counts ≥ 11.0 × 109/L were at greatest risk. Effective control of WBC counts is an important component of disease management and may reduce risk of thrombotic events in patients with PV.
Leukemias
Black patients with chronic lymphocytic leukemia tend to have worse overall survival and an earlier age at diagnosis with higher rates of adverse cytogenetics. This retrospective analysis of VHA patients compared black and nonblack patients. It found that black patients had worse survival compared to nonblack patients in a single health care delivery system, which limits differences in access to care. Black patients were younger and had shorter periods of observation and were more frequently given first-line fludarabine.
Induction chemotherapy (7+3) or high-dose ara-C-based (HIDAC) for acute myeloid leukemia (AML) results in prolonged neutropenia with a high risk of serious infection and attendant morbidity, and prolonged hospitalization. Researchers, including former AVAHO president Suman Kambhampati developed a randomized, open-label, controlled Phase 2 trial to study the effect of romyelocel-L in de novo patients receiving HIDAC or 7+3 induction therapy for reduction of fever and infection. The results from pooled and 7+3 cohorts, were previously presented, showing decrease in infections and days in hospital. The results from cohorts receiving HIDAC chemotherapy are presented here. The incidence of infections was decreased during the day 15-28 period and a decrease of three days in hospital stay was observed in de novo HIDAC AML subjects receiving romyelocel-L. Romyelocel-L may provide a new option to reduce infections in AML patients undergoing HIDAC induction therapy.
Multiple Myeloma
Two studies focused on racial disparities in multiple myeloma (MM), while another reported phase 2 data on a relapsed/refractory option.
This group of researchers found an absence of disparity in use of novel agents, no racial disparity was observed in overall survival between black and white patients with MM. Among patients aged < 65 years at diagnosis, the researchers observed a significantly lower age-adjusted risk of death for black patients compared with white patients. The difference in the younger population was not explained by access or utilization of resources. This analysis suggests that when healthcare access is neutralized, younger black patients may even have improved overall survival, which may indicate the possibility of genetic differences that may drive the disease biology and therapeutic outcome in AA patients.
Outcomes of Black Patients with Multiple Myeloma in the Veterans Health Administration
The second study found survival of black patients with MM was improved compared to non-blacks in the VHA, a national comprehensive care delivery system. Black patients also received similar therapies compared to non-blacks, while presenting at a younger age with more comorbidities. These results are strengthened after adjusting for treatments and patient characteristics not available in other large data studies. Despite increased incidence of MM in the black population, outcomes are improved, similar to other large studies of patients in the United States.
Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a phase 2 study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory MM who have received a first- or second-line treatment of lenalidomide-based therapy. In this trial, researchers (including those from VA facilities, Celgene, and multiple other locations) sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. The researchers reported that the triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed MM patients progressed and are or refractory to lenalidomide. According to the researchers the results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment.
With hundreds of sessions and thousands of abstracts, it can be difficult to wade through all the new findings to find the most significant and relevant findings. Federal Practitioner consulted with Association of VA Hematology/Oncology members who attended the meeting, VA researchers, and other sources to provide these nuggets you might have missed on lymphomas, white blood cells, leukemias, and multiple myeloma:
Lymphomas
This retrospective analysis of diffuse large B cell lymphoma (DCBL) patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the VA Audie Murphy Hospital in San Antonio, Texas was compared with patients with DLBCL who received R-CHOP in a community setting. According to the researchers, the response to initial treatment was inferior in the veteran population when compared with a patient population with similar demographics and having similar time from diagnosis to treatment. Veteran patients also had worse outcomes when compared with uninsured patients.
This retrospective analysis study identified 2,290 patients with follicular lymphoma treated in the Veterans Health Administration between 2006–2014 and detailed their staging, demographics, and comorbidities. The researchers found that maintenance therapy with rituximab was associated with an improvement in overall survival.
Another retrospective analysis of DBCL using VHA data examined the effectiveness of second-line chemotherapy and chemoimmunotherapy in patients aged ≥ 65 years. The researchers found 230 patients from 2001 to 2015 that met the inclusion criteria. According to the researchers, the overall survival was < 1 year and about half of the patients "did not receive or were not candidates for regimens typically used with intent for high-dose therapy and autologous transplant."
White Blood Cells
Cost-Effective Use of White Blood Cell Growth Factors in the Veterans Administration
This study analyzed the use of granulocyte colony-stimulating (G-CSF) vs pegfilgrastim in the UD Department of Veterans Affairs (VA) health care system. The researchers looked at the relative frequency of use of filgrastim, Tbo-filgrastim, Filgrastim-sndz and pegfilgrastim at 23 VA sites and found that uptake of biosimilar G-CSF has been extremely rapid. All sites are using biosimilar GCSF for all new patients; 6 of 23 sites were comfortable shifting current patients on branded G-CSF to the biosimilar.However, switching to a Tbo-filgrastim brought a cost savings of 2.2% that was "small compared to other clinical changes."
This analysis described the association between white blood cell (EBC) levels and occurrence of thrombotic events among patients with polycythemia vera (PV) using Veterans Health Administration claims data collected between 2005 and 2012. The researchers found A significant, positive association between increased WBC counts and occurrence of thrombotic events in patients with PV was observed in this study. Patients with WBC counts ≥ 8.5 × 109/L had a significantly increased risk of thrombotic events, and those with counts ≥ 11.0 × 109/L were at greatest risk. Effective control of WBC counts is an important component of disease management and may reduce risk of thrombotic events in patients with PV.
Leukemias
Black patients with chronic lymphocytic leukemia tend to have worse overall survival and an earlier age at diagnosis with higher rates of adverse cytogenetics. This retrospective analysis of VHA patients compared black and nonblack patients. It found that black patients had worse survival compared to nonblack patients in a single health care delivery system, which limits differences in access to care. Black patients were younger and had shorter periods of observation and were more frequently given first-line fludarabine.
Induction chemotherapy (7+3) or high-dose ara-C-based (HIDAC) for acute myeloid leukemia (AML) results in prolonged neutropenia with a high risk of serious infection and attendant morbidity, and prolonged hospitalization. Researchers, including former AVAHO president Suman Kambhampati developed a randomized, open-label, controlled Phase 2 trial to study the effect of romyelocel-L in de novo patients receiving HIDAC or 7+3 induction therapy for reduction of fever and infection. The results from pooled and 7+3 cohorts, were previously presented, showing decrease in infections and days in hospital. The results from cohorts receiving HIDAC chemotherapy are presented here. The incidence of infections was decreased during the day 15-28 period and a decrease of three days in hospital stay was observed in de novo HIDAC AML subjects receiving romyelocel-L. Romyelocel-L may provide a new option to reduce infections in AML patients undergoing HIDAC induction therapy.
Multiple Myeloma
Two studies focused on racial disparities in multiple myeloma (MM), while another reported phase 2 data on a relapsed/refractory option.
This group of researchers found an absence of disparity in use of novel agents, no racial disparity was observed in overall survival between black and white patients with MM. Among patients aged < 65 years at diagnosis, the researchers observed a significantly lower age-adjusted risk of death for black patients compared with white patients. The difference in the younger population was not explained by access or utilization of resources. This analysis suggests that when healthcare access is neutralized, younger black patients may even have improved overall survival, which may indicate the possibility of genetic differences that may drive the disease biology and therapeutic outcome in AA patients.
Outcomes of Black Patients with Multiple Myeloma in the Veterans Health Administration
The second study found survival of black patients with MM was improved compared to non-blacks in the VHA, a national comprehensive care delivery system. Black patients also received similar therapies compared to non-blacks, while presenting at a younger age with more comorbidities. These results are strengthened after adjusting for treatments and patient characteristics not available in other large data studies. Despite increased incidence of MM in the black population, outcomes are improved, similar to other large studies of patients in the United States.
Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a phase 2 study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory MM who have received a first- or second-line treatment of lenalidomide-based therapy. In this trial, researchers (including those from VA facilities, Celgene, and multiple other locations) sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. The researchers reported that the triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed MM patients progressed and are or refractory to lenalidomide. According to the researchers the results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment.
With hundreds of sessions and thousands of abstracts, it can be difficult to wade through all the new findings to find the most significant and relevant findings. Federal Practitioner consulted with Association of VA Hematology/Oncology members who attended the meeting, VA researchers, and other sources to provide these nuggets you might have missed on lymphomas, white blood cells, leukemias, and multiple myeloma:
Lymphomas
This retrospective analysis of diffuse large B cell lymphoma (DCBL) patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at the VA Audie Murphy Hospital in San Antonio, Texas was compared with patients with DLBCL who received R-CHOP in a community setting. According to the researchers, the response to initial treatment was inferior in the veteran population when compared with a patient population with similar demographics and having similar time from diagnosis to treatment. Veteran patients also had worse outcomes when compared with uninsured patients.
This retrospective analysis study identified 2,290 patients with follicular lymphoma treated in the Veterans Health Administration between 2006–2014 and detailed their staging, demographics, and comorbidities. The researchers found that maintenance therapy with rituximab was associated with an improvement in overall survival.
Another retrospective analysis of DBCL using VHA data examined the effectiveness of second-line chemotherapy and chemoimmunotherapy in patients aged ≥ 65 years. The researchers found 230 patients from 2001 to 2015 that met the inclusion criteria. According to the researchers, the overall survival was < 1 year and about half of the patients "did not receive or were not candidates for regimens typically used with intent for high-dose therapy and autologous transplant."
White Blood Cells
Cost-Effective Use of White Blood Cell Growth Factors in the Veterans Administration
This study analyzed the use of granulocyte colony-stimulating (G-CSF) vs pegfilgrastim in the UD Department of Veterans Affairs (VA) health care system. The researchers looked at the relative frequency of use of filgrastim, Tbo-filgrastim, Filgrastim-sndz and pegfilgrastim at 23 VA sites and found that uptake of biosimilar G-CSF has been extremely rapid. All sites are using biosimilar GCSF for all new patients; 6 of 23 sites were comfortable shifting current patients on branded G-CSF to the biosimilar.However, switching to a Tbo-filgrastim brought a cost savings of 2.2% that was "small compared to other clinical changes."
This analysis described the association between white blood cell (EBC) levels and occurrence of thrombotic events among patients with polycythemia vera (PV) using Veterans Health Administration claims data collected between 2005 and 2012. The researchers found A significant, positive association between increased WBC counts and occurrence of thrombotic events in patients with PV was observed in this study. Patients with WBC counts ≥ 8.5 × 109/L had a significantly increased risk of thrombotic events, and those with counts ≥ 11.0 × 109/L were at greatest risk. Effective control of WBC counts is an important component of disease management and may reduce risk of thrombotic events in patients with PV.
Leukemias
Black patients with chronic lymphocytic leukemia tend to have worse overall survival and an earlier age at diagnosis with higher rates of adverse cytogenetics. This retrospective analysis of VHA patients compared black and nonblack patients. It found that black patients had worse survival compared to nonblack patients in a single health care delivery system, which limits differences in access to care. Black patients were younger and had shorter periods of observation and were more frequently given first-line fludarabine.
Induction chemotherapy (7+3) or high-dose ara-C-based (HIDAC) for acute myeloid leukemia (AML) results in prolonged neutropenia with a high risk of serious infection and attendant morbidity, and prolonged hospitalization. Researchers, including former AVAHO president Suman Kambhampati developed a randomized, open-label, controlled Phase 2 trial to study the effect of romyelocel-L in de novo patients receiving HIDAC or 7+3 induction therapy for reduction of fever and infection. The results from pooled and 7+3 cohorts, were previously presented, showing decrease in infections and days in hospital. The results from cohorts receiving HIDAC chemotherapy are presented here. The incidence of infections was decreased during the day 15-28 period and a decrease of three days in hospital stay was observed in de novo HIDAC AML subjects receiving romyelocel-L. Romyelocel-L may provide a new option to reduce infections in AML patients undergoing HIDAC induction therapy.
Multiple Myeloma
Two studies focused on racial disparities in multiple myeloma (MM), while another reported phase 2 data on a relapsed/refractory option.
This group of researchers found an absence of disparity in use of novel agents, no racial disparity was observed in overall survival between black and white patients with MM. Among patients aged < 65 years at diagnosis, the researchers observed a significantly lower age-adjusted risk of death for black patients compared with white patients. The difference in the younger population was not explained by access or utilization of resources. This analysis suggests that when healthcare access is neutralized, younger black patients may even have improved overall survival, which may indicate the possibility of genetic differences that may drive the disease biology and therapeutic outcome in AA patients.
Outcomes of Black Patients with Multiple Myeloma in the Veterans Health Administration
The second study found survival of black patients with MM was improved compared to non-blacks in the VHA, a national comprehensive care delivery system. Black patients also received similar therapies compared to non-blacks, while presenting at a younger age with more comorbidities. These results are strengthened after adjusting for treatments and patient characteristics not available in other large data studies. Despite increased incidence of MM in the black population, outcomes are improved, similar to other large studies of patients in the United States.
Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a phase 2 study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory MM who have received a first- or second-line treatment of lenalidomide-based therapy. In this trial, researchers (including those from VA facilities, Celgene, and multiple other locations) sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. The researchers reported that the triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed MM patients progressed and are or refractory to lenalidomide. According to the researchers the results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment.
2018: A banner year for hematology drug approvals
SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.
, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.
These include six new approvals for first-line treatment, and eight for pediatric indications, he said.
Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.
“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”
Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.
SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.
, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.
These include six new approvals for first-line treatment, and eight for pediatric indications, he said.
Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.
“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”
Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.
SAN DIEGO – It was banner year for new hematology drug approvals, according to R. Angelo de Claro, MD, of the Food and Drug Administration.
, including 12 first-time approvals, 5 new biosimilars, and 15 new indications for previously approved drugs, Dr. de Claro, clinical team leader in the FDA’s division of hematology products in Silver Spring, Md., said during an overview of the approvals at the annual meeting of the American Society of Hematology.
These include six new approvals for first-line treatment, and eight for pediatric indications, he said.
Highlights were discussed at two ASH-FDA joint symposia at the meeting, including one focused on the malignant hematology approvals, and another on the nonmalignant hematology approvals. In a video interview, Dr. de Claro provides some additional insight into their importance and about what might lie ahead.
“I think what’s exciting is that you have drug development occurring in more common conditions such as chronic lymphocytic leukemia, as well as in rare conditions, including hairy cell leukemia – and the first-ever approval in hemophagocytic lymphohistiocytosis,” he said. “It’s been very busy at the FDA; stay tuned ... the year’s not done yet. There could be more coming and we certainly anticipate more applications in the future.”
Dr. de Claro is an FDA employee. He reported having no other relevant disclosures.
REPORTING FROM ASH 2018
CLL resistance mechanism to venetoclax identified
SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.
The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.
“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.
The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.
The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.
Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.
To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.
In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.
They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.
In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.
Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.
“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.
In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.
The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.
SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.
SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.
The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.
“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.
The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.
The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.
Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.
To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.
In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.
They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.
In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.
Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.
“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.
In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.
The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.
SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.
SAN DIEGO – A recurrent mutation in BCL2, the therapeutic target of venetoclax (Venclexta), appears to be a major contributor to drug resistance in patients with chronic lymphocytic leukemia (CLL), investigators reported.
The mutation has been detected in some patients with CLL up to 2 years before resistance to venetoclax actually develops, said lead author Piers Blombery, MBBS, from the Peter MacCallum Cancer Center in Melbourne.
“We have identified the first acquired BCL2 mutation developed in patients clinically treated with venetoclax,” he said in a late-breaking oral abstract session at the annual meeting of the American Society of Hematology.
The mutation, which the investigators have labeled BCL2 Gly101Val, “is a recurrent and frequent mediator of resistance and may be detected years before clinical relapse occurs,” he added.
The paper was published online in Cancer Discovery (2018 Dec 4. doi: 10.1158/2159-8290.CD-18-1119) to coincide with the presentation at ASH.
Despite the demonstrated efficacy of venetoclax as continuous therapy in patients with relapsed or refractory CLL, the majority of patients experience disease progression, prompting the investigators to explore molecular mechanisms of secondary resistance.
To do this, they analyzed paired samples from 15 patients with CLL, enrolled in clinical trials of venetoclax, collected both before the start of venetoclax therapy and at the time of disease progression.
In seven of the patients, they identified a novel mutation that showed up at the time of progression, but was absent from the pre-venetoclax samples. The mutation first became detectable from about 19 to 42 months after the start of therapy and preceded clinical progression by as much as 25 months, the investigators found.
They pinned the mutation down to the BH3-binding groove on BCL2, the same molecular site targeted by venetoclax. They found that the mutation was not present in samples from 96 patients with venetoclax-naive CLL nor in any other B-cell malignancies. Searches for references to the mutation in both a cancer database (COSMIC) and a population database (gnomAD) came up empty.
In other experiments, they determined that cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax, and that in the presence of venetoclax in vitro, BCL2 Gly101Val-expressing cells have a growth advantage, compared with wild type cells.
Additionally, they showed that the mutation results in impaired venetoclax binding in vitro.
“BCL2 Gly101Val is observed subclonally, implicating multiple mechanisms of venetoclax resistance in the same patient,” Dr. Blombery said.
In an interview, Dr. Blombery said that the identification of the resistance mutation is a strong rationale for using combination therapy to treat patients with relapsed or refractory CLL to help prevent or attenuate selection pressures that lead to resistance.
The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.
SOURCE: Blombery P et al. ASH 2018, Abstract LBA-7.
REPORTING FROM ASH 2018
Key clinical point:
Major finding: The mutation was identified in samples from seven patients after venetoclax therapy, but not in any of the pretherapy samples.
Study details: Genetic analysis of CLL mutations in 15 patients enrolled in clinical trials of venetoclax.
Disclosures: The investigators were supported by the Wilson Center for Lymphoma Genomics, Snowdome Foundation, National Health Medical Research Council, Leukemia and Lymphoma Society, Leukemia Foundation, Cancer Council of Victoria, and Australian Cancer Research Foundation. Dr. Blombery reported having no relevant disclosures.
Source: Blombery P et al. ASH 2018, Abstract LBA-7.
FDA approves rituximab biosimilar for lymphoma
(NHL).
Celltrion’s Truxima (rituximab-abbs) is a biosimilar of Genentech’s Rituxan (rituximab) and the first biosimilar approved in the United States to treat NHL.
Truxima (formerly CT-P10) is approved to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy. Truxima is approved as a single agent to treat relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL. Truxima is approved in combination with first-line chemotherapy to treat previously untreated follicular, CD20-positive, B-cell NHL.
Truxima is approved as single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response to a rituximab product in combination with chemotherapy. Truxima also is approved as a single agent to treat nonprogressing, low-grade, CD20-positive, B-cell NHL after first-line treatment with cyclophosphamide, vincristine, and prednisone.The label for Truxima contains a boxed warning detailing the risk of fatal infusion reactions, severe skin and mouth reactions (some with fatal outcomes), hepatitis B virus reactivation that may cause serious liver problems (including liver failure and death), and progressive multifocal leukoencephalopathy.
The FDA said its approval of Truxima is “based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrates Truxima is biosimilar to Rituxan.”
Findings from a phase 3 trial suggested that Truxima is equivalent to the reference product in patients with low-tumor-burden follicular lymphoma (Lancet Haematol. 2018 Nov;5[11]:e543-53).
(NHL).
Celltrion’s Truxima (rituximab-abbs) is a biosimilar of Genentech’s Rituxan (rituximab) and the first biosimilar approved in the United States to treat NHL.
Truxima (formerly CT-P10) is approved to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy. Truxima is approved as a single agent to treat relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL. Truxima is approved in combination with first-line chemotherapy to treat previously untreated follicular, CD20-positive, B-cell NHL.
Truxima is approved as single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response to a rituximab product in combination with chemotherapy. Truxima also is approved as a single agent to treat nonprogressing, low-grade, CD20-positive, B-cell NHL after first-line treatment with cyclophosphamide, vincristine, and prednisone.The label for Truxima contains a boxed warning detailing the risk of fatal infusion reactions, severe skin and mouth reactions (some with fatal outcomes), hepatitis B virus reactivation that may cause serious liver problems (including liver failure and death), and progressive multifocal leukoencephalopathy.
The FDA said its approval of Truxima is “based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrates Truxima is biosimilar to Rituxan.”
Findings from a phase 3 trial suggested that Truxima is equivalent to the reference product in patients with low-tumor-burden follicular lymphoma (Lancet Haematol. 2018 Nov;5[11]:e543-53).
(NHL).
Celltrion’s Truxima (rituximab-abbs) is a biosimilar of Genentech’s Rituxan (rituximab) and the first biosimilar approved in the United States to treat NHL.
Truxima (formerly CT-P10) is approved to treat adults with CD20-positive, B-cell NHL, either as a single agent or in combination with chemotherapy. Truxima is approved as a single agent to treat relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL. Truxima is approved in combination with first-line chemotherapy to treat previously untreated follicular, CD20-positive, B-cell NHL.
Truxima is approved as single-agent maintenance therapy in patients with follicular, CD20-positive, B-cell NHL who achieve a complete or partial response to a rituximab product in combination with chemotherapy. Truxima also is approved as a single agent to treat nonprogressing, low-grade, CD20-positive, B-cell NHL after first-line treatment with cyclophosphamide, vincristine, and prednisone.The label for Truxima contains a boxed warning detailing the risk of fatal infusion reactions, severe skin and mouth reactions (some with fatal outcomes), hepatitis B virus reactivation that may cause serious liver problems (including liver failure and death), and progressive multifocal leukoencephalopathy.
The FDA said its approval of Truxima is “based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic data, clinical immunogenicity data, and other clinical data that demonstrates Truxima is biosimilar to Rituxan.”
Findings from a phase 3 trial suggested that Truxima is equivalent to the reference product in patients with low-tumor-burden follicular lymphoma (Lancet Haematol. 2018 Nov;5[11]:e543-53).
FDA expands approval of brentuximab vedotin to PTCL
The , marking the first FDA approval of a treatment for newly-diagnosed PTCL.
The drug, which is marketed by Seattle Genetics as Adcetris, is a monoclonal antibody that binds to CD30 protein found on some cancer cells.
It was previously approved for adult patients with untreated stage III or IV classical Hodgkin lymphoma (cHL), cHL after relapse, cHL after stem cell transplant in patients at high risk for relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after other treatments fail, and primary cutaneous ALCL or CD30-expressing mycosis fungoides after other treatments fail.
The expanded approval, which followed the granting of Priority Review and Breakthrough Therapy designations for the supplemental Biologic License Application, was made using the FDA’s new Real-Time Oncology Review pilot program (RTOR). This program allows for data review and communication with a sponsor prior to official application submission with the goal of speeding up the review process.
The brentuximab vedotin approval now extends to previously untreated systemic ALCL and other CD30-expressing PTCLs in combination with chemotherapy.
Approval was based on the ECHELON-2 clinical trial involving 452 patients, which demonstrated improved progression-free survival (PFS) in patients with certain types of PTCL who were treated first-line with either brentuximab vedotin plus chemotherapy with cyclophosphamide, doxorubicin, prednisone (CHP), or standard chemotherapy with CHP and vincristine (CHOP). Median PFS was 48 months vs. 21 months in the groups, respectively (hazard ratio, 0.71).
The FDA advises health care providers to “monitor patients for infusion reactions, life-threatening allergic reactions (anaphylaxis), neuropathy, fever, gastrointestinal complications, and infections,” according to a press release announcing the approval, which also states that patients should be monitored for tumor lysis syndrome, serious skin reactions, pulmonary toxicity, and hepatotoxicity.
The drug may cause harm to a developing fetus or newborn and should not be used in women who are pregnant or breastfeeding. A Boxed Warning regarding risk of progressive multifocal leukoencephalopathy is also included in the prescribing information.
The current standard of care for initial treatment of PTCL is multiagent chemotherapy – a treatment that “has not significantly changed in decades and is too often unsuccessful in leading to long-term remissions, underscoring the need for new treatments, ” Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York, said in a statement issued by Seattle Genetics.
“With this approval, clinicians have the opportunity to transform the way newly diagnosed CD30-expressing PTCL patients are treated,” Dr. Horwitz said.
The ECHELON-2 data will be presented at the American Society of Hematology annual meeting in San Diego on Monday, Dec. 3, 2018.
The , marking the first FDA approval of a treatment for newly-diagnosed PTCL.
The drug, which is marketed by Seattle Genetics as Adcetris, is a monoclonal antibody that binds to CD30 protein found on some cancer cells.
It was previously approved for adult patients with untreated stage III or IV classical Hodgkin lymphoma (cHL), cHL after relapse, cHL after stem cell transplant in patients at high risk for relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after other treatments fail, and primary cutaneous ALCL or CD30-expressing mycosis fungoides after other treatments fail.
The expanded approval, which followed the granting of Priority Review and Breakthrough Therapy designations for the supplemental Biologic License Application, was made using the FDA’s new Real-Time Oncology Review pilot program (RTOR). This program allows for data review and communication with a sponsor prior to official application submission with the goal of speeding up the review process.
The brentuximab vedotin approval now extends to previously untreated systemic ALCL and other CD30-expressing PTCLs in combination with chemotherapy.
Approval was based on the ECHELON-2 clinical trial involving 452 patients, which demonstrated improved progression-free survival (PFS) in patients with certain types of PTCL who were treated first-line with either brentuximab vedotin plus chemotherapy with cyclophosphamide, doxorubicin, prednisone (CHP), or standard chemotherapy with CHP and vincristine (CHOP). Median PFS was 48 months vs. 21 months in the groups, respectively (hazard ratio, 0.71).
The FDA advises health care providers to “monitor patients for infusion reactions, life-threatening allergic reactions (anaphylaxis), neuropathy, fever, gastrointestinal complications, and infections,” according to a press release announcing the approval, which also states that patients should be monitored for tumor lysis syndrome, serious skin reactions, pulmonary toxicity, and hepatotoxicity.
The drug may cause harm to a developing fetus or newborn and should not be used in women who are pregnant or breastfeeding. A Boxed Warning regarding risk of progressive multifocal leukoencephalopathy is also included in the prescribing information.
The current standard of care for initial treatment of PTCL is multiagent chemotherapy – a treatment that “has not significantly changed in decades and is too often unsuccessful in leading to long-term remissions, underscoring the need for new treatments, ” Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York, said in a statement issued by Seattle Genetics.
“With this approval, clinicians have the opportunity to transform the way newly diagnosed CD30-expressing PTCL patients are treated,” Dr. Horwitz said.
The ECHELON-2 data will be presented at the American Society of Hematology annual meeting in San Diego on Monday, Dec. 3, 2018.
The , marking the first FDA approval of a treatment for newly-diagnosed PTCL.
The drug, which is marketed by Seattle Genetics as Adcetris, is a monoclonal antibody that binds to CD30 protein found on some cancer cells.
It was previously approved for adult patients with untreated stage III or IV classical Hodgkin lymphoma (cHL), cHL after relapse, cHL after stem cell transplant in patients at high risk for relapse or progression, systemic anaplastic large cell lymphoma (ALCL) after other treatments fail, and primary cutaneous ALCL or CD30-expressing mycosis fungoides after other treatments fail.
The expanded approval, which followed the granting of Priority Review and Breakthrough Therapy designations for the supplemental Biologic License Application, was made using the FDA’s new Real-Time Oncology Review pilot program (RTOR). This program allows for data review and communication with a sponsor prior to official application submission with the goal of speeding up the review process.
The brentuximab vedotin approval now extends to previously untreated systemic ALCL and other CD30-expressing PTCLs in combination with chemotherapy.
Approval was based on the ECHELON-2 clinical trial involving 452 patients, which demonstrated improved progression-free survival (PFS) in patients with certain types of PTCL who were treated first-line with either brentuximab vedotin plus chemotherapy with cyclophosphamide, doxorubicin, prednisone (CHP), or standard chemotherapy with CHP and vincristine (CHOP). Median PFS was 48 months vs. 21 months in the groups, respectively (hazard ratio, 0.71).
The FDA advises health care providers to “monitor patients for infusion reactions, life-threatening allergic reactions (anaphylaxis), neuropathy, fever, gastrointestinal complications, and infections,” according to a press release announcing the approval, which also states that patients should be monitored for tumor lysis syndrome, serious skin reactions, pulmonary toxicity, and hepatotoxicity.
The drug may cause harm to a developing fetus or newborn and should not be used in women who are pregnant or breastfeeding. A Boxed Warning regarding risk of progressive multifocal leukoencephalopathy is also included in the prescribing information.
The current standard of care for initial treatment of PTCL is multiagent chemotherapy – a treatment that “has not significantly changed in decades and is too often unsuccessful in leading to long-term remissions, underscoring the need for new treatments, ” Steven Horwitz, MD, of Memorial Sloan Kettering Cancer Center, New York, said in a statement issued by Seattle Genetics.
“With this approval, clinicians have the opportunity to transform the way newly diagnosed CD30-expressing PTCL patients are treated,” Dr. Horwitz said.
The ECHELON-2 data will be presented at the American Society of Hematology annual meeting in San Diego on Monday, Dec. 3, 2018.
Bortezomib may unlock resistance in WM with mutations
The use of bortezomib may help overcome treatment resistance in patients with Waldenström macroglobulinemia (WM) with CXCR4 mutations, according to new research.
Romanos Sklavenitis-Pistofidis, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues compared the effects of treatment with bortezomib/rituximab in patients with WM based on their CXCR4 mutation status. They found no significant difference in progression-free survival (Log-rank, P = .994) or overall survival (Log-rank, P = .407) when comparing patients who have CXCR4 mutations with those who have CXCR4 wild type.
“We report for the first time that a bortezomib-based combination is impervious to the impact of CXCR4 mutations in a cohort of patients with WM,” the researchers wrote in Blood. “Previously, we had shown this to be true in WM cell lines, whereby genetically engineering BCWM.1 and MWCL-1 to overexpress CXCR4 had no impact on bortezomib resistance.”
The researchers noted, however, that the mechanism at work may be different than that seen with bortezomib in other cancers.
“Different experiments have linked CXCR4 expression and bortezomib in a variety of ways in other hematological malignancies, including multiple myeloma. However, despite the complicated association in those cancer types, in WM there seems to be a consistently neutral effect of CXCR4 mutations on bortezomib resistance in both cell line and patient data,” they wrote.
The researchers recommended that the theory be tested in a prospective trial of bortezomib-based therapy in WM patients with CXCR4 mutations. Another question to be investigated, they pointed out, is the role of rituximab in the survival results seen in the current analysis.
The study included 63 patients with WM who were treated with bortezomib/rituximab either as upfront treatment or in the relapsed/refractory setting as part of a phase 2 trial.
Bortezomib was given by IV weekly at 1.6 mg/m2 for six cycles and rituximab was given at 375 mg/m2 during cycles one and four. Patients were taken off therapy after two cycles if they had progressive disease.
The researchers excluded 20 patients from the study because of a lack of material for genotyping. However, they noted that their clinical characteristics were not different from those patients who were included.
Out of 43 patients who were genotyped for CXCR4, 17 patients had a mutation. All patients who carried a CXCR4 mutation also had MYD88 L265P. Ten patients had frameshift mutations, one patient had a nonsense mutation, and six patients had missense mutations. The median follow-up of the analysis was 90.7 months.
The researchers repeated the analysis after excluding six patients with missense mutations and accounting for different treatment settings and found that survival remained unchanged.
The study was supported by the National Institutes of Health, the Leukemia and Lymphoma Society, and the International Waldenström Macroglobulinemia Foundation. One of the authors reported consulting and research funding from Takeda, which markets bortezomib, and other companies.
SOURCE: Sklavenitis-Pistofidis R et al. Blood. 2018 Oct 26. doi: 10.1182/blood-2018-07-863241.
The use of bortezomib may help overcome treatment resistance in patients with Waldenström macroglobulinemia (WM) with CXCR4 mutations, according to new research.
Romanos Sklavenitis-Pistofidis, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues compared the effects of treatment with bortezomib/rituximab in patients with WM based on their CXCR4 mutation status. They found no significant difference in progression-free survival (Log-rank, P = .994) or overall survival (Log-rank, P = .407) when comparing patients who have CXCR4 mutations with those who have CXCR4 wild type.
“We report for the first time that a bortezomib-based combination is impervious to the impact of CXCR4 mutations in a cohort of patients with WM,” the researchers wrote in Blood. “Previously, we had shown this to be true in WM cell lines, whereby genetically engineering BCWM.1 and MWCL-1 to overexpress CXCR4 had no impact on bortezomib resistance.”
The researchers noted, however, that the mechanism at work may be different than that seen with bortezomib in other cancers.
“Different experiments have linked CXCR4 expression and bortezomib in a variety of ways in other hematological malignancies, including multiple myeloma. However, despite the complicated association in those cancer types, in WM there seems to be a consistently neutral effect of CXCR4 mutations on bortezomib resistance in both cell line and patient data,” they wrote.
The researchers recommended that the theory be tested in a prospective trial of bortezomib-based therapy in WM patients with CXCR4 mutations. Another question to be investigated, they pointed out, is the role of rituximab in the survival results seen in the current analysis.
The study included 63 patients with WM who were treated with bortezomib/rituximab either as upfront treatment or in the relapsed/refractory setting as part of a phase 2 trial.
Bortezomib was given by IV weekly at 1.6 mg/m2 for six cycles and rituximab was given at 375 mg/m2 during cycles one and four. Patients were taken off therapy after two cycles if they had progressive disease.
The researchers excluded 20 patients from the study because of a lack of material for genotyping. However, they noted that their clinical characteristics were not different from those patients who were included.
Out of 43 patients who were genotyped for CXCR4, 17 patients had a mutation. All patients who carried a CXCR4 mutation also had MYD88 L265P. Ten patients had frameshift mutations, one patient had a nonsense mutation, and six patients had missense mutations. The median follow-up of the analysis was 90.7 months.
The researchers repeated the analysis after excluding six patients with missense mutations and accounting for different treatment settings and found that survival remained unchanged.
The study was supported by the National Institutes of Health, the Leukemia and Lymphoma Society, and the International Waldenström Macroglobulinemia Foundation. One of the authors reported consulting and research funding from Takeda, which markets bortezomib, and other companies.
SOURCE: Sklavenitis-Pistofidis R et al. Blood. 2018 Oct 26. doi: 10.1182/blood-2018-07-863241.
The use of bortezomib may help overcome treatment resistance in patients with Waldenström macroglobulinemia (WM) with CXCR4 mutations, according to new research.
Romanos Sklavenitis-Pistofidis, MD, of the Dana-Farber Cancer Institute in Boston, and his colleagues compared the effects of treatment with bortezomib/rituximab in patients with WM based on their CXCR4 mutation status. They found no significant difference in progression-free survival (Log-rank, P = .994) or overall survival (Log-rank, P = .407) when comparing patients who have CXCR4 mutations with those who have CXCR4 wild type.
“We report for the first time that a bortezomib-based combination is impervious to the impact of CXCR4 mutations in a cohort of patients with WM,” the researchers wrote in Blood. “Previously, we had shown this to be true in WM cell lines, whereby genetically engineering BCWM.1 and MWCL-1 to overexpress CXCR4 had no impact on bortezomib resistance.”
The researchers noted, however, that the mechanism at work may be different than that seen with bortezomib in other cancers.
“Different experiments have linked CXCR4 expression and bortezomib in a variety of ways in other hematological malignancies, including multiple myeloma. However, despite the complicated association in those cancer types, in WM there seems to be a consistently neutral effect of CXCR4 mutations on bortezomib resistance in both cell line and patient data,” they wrote.
The researchers recommended that the theory be tested in a prospective trial of bortezomib-based therapy in WM patients with CXCR4 mutations. Another question to be investigated, they pointed out, is the role of rituximab in the survival results seen in the current analysis.
The study included 63 patients with WM who were treated with bortezomib/rituximab either as upfront treatment or in the relapsed/refractory setting as part of a phase 2 trial.
Bortezomib was given by IV weekly at 1.6 mg/m2 for six cycles and rituximab was given at 375 mg/m2 during cycles one and four. Patients were taken off therapy after two cycles if they had progressive disease.
The researchers excluded 20 patients from the study because of a lack of material for genotyping. However, they noted that their clinical characteristics were not different from those patients who were included.
Out of 43 patients who were genotyped for CXCR4, 17 patients had a mutation. All patients who carried a CXCR4 mutation also had MYD88 L265P. Ten patients had frameshift mutations, one patient had a nonsense mutation, and six patients had missense mutations. The median follow-up of the analysis was 90.7 months.
The researchers repeated the analysis after excluding six patients with missense mutations and accounting for different treatment settings and found that survival remained unchanged.
The study was supported by the National Institutes of Health, the Leukemia and Lymphoma Society, and the International Waldenström Macroglobulinemia Foundation. One of the authors reported consulting and research funding from Takeda, which markets bortezomib, and other companies.
SOURCE: Sklavenitis-Pistofidis R et al. Blood. 2018 Oct 26. doi: 10.1182/blood-2018-07-863241.
FROM BLOOD
Key clinical point:
Major finding: Progression-free and overall survival were not significantly different between WM patients with CXCR4 mutations and those with CXCR4 wild type (log-rank, P = .994 and P = .407, respectively).
Study details: An analysis of 43 WM patients treated with bortezomib/rituximab and genotyped to determine CXCR4 mutation status.
Disclosures: The study was supported by the National Institutes of Health, the Leukemia and Lymphoma Society, and the International Waldenström Macroglobulinemia Foundation. One of the authors reported consulting and research funding from Takeda, which markets bortezomib, and other companies.
Source: Sklavenitis-Pistofidis R et al. Blood. 2018 Oct 26. doi: 10.1182/blood-2018-07-863241.
Azacitidine-nivolumab combo 'encouraging' in AML
The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.
The overall response rate was 33%, and the median overall survival (OS) was 6.3 months. However, the researchers identified factors associated with improved response and survival that could be used to select patients for this treatment.
A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment related.
Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported these results in Cancer Discovery.
The trial included 70 patients with a median age of 70 years. More than half of the patients (56%) had de novo AML, and 44% had secondary AML. The median number of prior therapies was two; 64% of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).
For this trial, patients received azacitidine at 75 mg/m2 on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was three. Patients had a median time on study of 3.5 months and reasons for discontinuation included primary refractory disease, relapse after initial response, proceeding to SCT, patient preference, and death.
The most common treatment-related, nonhematologic AEs were constipation, diarrhea, pneumonitis, nausea, and lung infection. The rate of immune-related AEs was 25% (n = 18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4); 14 responded to steroids and were safely rechallenged with nivolumab, according to the researchers.
Nine patients (13%) discontinued nivolumab (but continued with azacitidine) because of AEs. Two patients died of AEs that were considered possibly related to treatment. One death was caused by progressive pneumonia/pneumonitis, and one was caused by hemophagocytic lymphohistiocytosis.
The overall response rate was 33% (n = 23), with 4 patients achieving a complete response (CR) and 11 achieving a CR with incomplete count recovery (CRi). One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.
The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. Additionally, a higher frequency of pretherapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.
“In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” Dr. Daver said in a statement.
At a median follow-up of 21.4 months, 81% of patients (n = 57) had died; 16 died on study treatment and 41 died after discontinuation. The median OS overall was 6.3 months, and the median event-free survival was 4.5 months.
The median OS was 16.1 months in patients with CR/CRi, partial response, hematologic improvement, or stable disease and 4.1 months in nonresponders (P less than .0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P less than .001).
The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.
Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory AML.
“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Dr. Daver said.
This research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Individual researchers also reported financial relationships with Bristol-Myers Squibb.
SOURCE: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.
The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.
The overall response rate was 33%, and the median overall survival (OS) was 6.3 months. However, the researchers identified factors associated with improved response and survival that could be used to select patients for this treatment.
A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment related.
Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported these results in Cancer Discovery.
The trial included 70 patients with a median age of 70 years. More than half of the patients (56%) had de novo AML, and 44% had secondary AML. The median number of prior therapies was two; 64% of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).
For this trial, patients received azacitidine at 75 mg/m2 on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was three. Patients had a median time on study of 3.5 months and reasons for discontinuation included primary refractory disease, relapse after initial response, proceeding to SCT, patient preference, and death.
The most common treatment-related, nonhematologic AEs were constipation, diarrhea, pneumonitis, nausea, and lung infection. The rate of immune-related AEs was 25% (n = 18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4); 14 responded to steroids and were safely rechallenged with nivolumab, according to the researchers.
Nine patients (13%) discontinued nivolumab (but continued with azacitidine) because of AEs. Two patients died of AEs that were considered possibly related to treatment. One death was caused by progressive pneumonia/pneumonitis, and one was caused by hemophagocytic lymphohistiocytosis.
The overall response rate was 33% (n = 23), with 4 patients achieving a complete response (CR) and 11 achieving a CR with incomplete count recovery (CRi). One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.
The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. Additionally, a higher frequency of pretherapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.
“In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” Dr. Daver said in a statement.
At a median follow-up of 21.4 months, 81% of patients (n = 57) had died; 16 died on study treatment and 41 died after discontinuation. The median OS overall was 6.3 months, and the median event-free survival was 4.5 months.
The median OS was 16.1 months in patients with CR/CRi, partial response, hematologic improvement, or stable disease and 4.1 months in nonresponders (P less than .0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P less than .001).
The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.
Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory AML.
“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Dr. Daver said.
This research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Individual researchers also reported financial relationships with Bristol-Myers Squibb.
SOURCE: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.
The combination of azacitidine and nivolumab produced “encouraging” results in a phase 2 trial of patients with relapsed or refractory acute myeloid leukemia (AML), according to researchers.
The overall response rate was 33%, and the median overall survival (OS) was 6.3 months. However, the researchers identified factors associated with improved response and survival that could be used to select patients for this treatment.
A quarter of patients on this trial had immune-related adverse events (AEs) that were considered related to treatment, and two patients died of AEs that may have been treatment related.
Naval Daver, MD, of the University of Texas MD Anderson Cancer Center, Houston, and his colleagues reported these results in Cancer Discovery.
The trial included 70 patients with a median age of 70 years. More than half of the patients (56%) had de novo AML, and 44% had secondary AML. The median number of prior therapies was two; 64% of patients had received hypomethylating agents, 47% had received targeted therapies, and 19% had received allogeneic stem cell transplant (SCT).
For this trial, patients received azacitidine at 75 mg/m2 on days 1 to 7 and nivolumab at 3 mg/kg on days 1 and 14 of each cycle. The median number of cycles was three. Patients had a median time on study of 3.5 months and reasons for discontinuation included primary refractory disease, relapse after initial response, proceeding to SCT, patient preference, and death.
The most common treatment-related, nonhematologic AEs were constipation, diarrhea, pneumonitis, nausea, and lung infection. The rate of immune-related AEs was 25% (n = 18), with grade 2-4 immune-related AEs occurring in 16 patients (8 with grade 3-4); 14 responded to steroids and were safely rechallenged with nivolumab, according to the researchers.
Nine patients (13%) discontinued nivolumab (but continued with azacitidine) because of AEs. Two patients died of AEs that were considered possibly related to treatment. One death was caused by progressive pneumonia/pneumonitis, and one was caused by hemophagocytic lymphohistiocytosis.
The overall response rate was 33% (n = 23), with 4 patients achieving a complete response (CR) and 11 achieving a CR with incomplete count recovery (CRi). One patient had a partial response, and seven had hematologic improvement in one or more parameter maintained for more than 6 months. Six patients had stable disease lasting more than 6 months.
The researchers noted that the response rate was higher among patients who had not received prior treatment with hypomethylating agents. Additionally, a higher frequency of pretherapy CD3 and CD8 cells in the bone marrow or peripheral blood appeared to predict response.
“In particular, CD3 appeared to have a high sensitivity and specificity rate for predicting response, indicating it might serve as a reliable biomarker for selecting patients for this combination therapy,” Dr. Daver said in a statement.
At a median follow-up of 21.4 months, 81% of patients (n = 57) had died; 16 died on study treatment and 41 died after discontinuation. The median OS overall was 6.3 months, and the median event-free survival was 4.5 months.
The median OS was 16.1 months in patients with CR/CRi, partial response, hematologic improvement, or stable disease and 4.1 months in nonresponders (P less than .0001). This difference was still significant after the researchers censored the three patients who had gone on to SCT in CR/CRi (P less than .001).
The researchers also found that being in first salvage was associated with improved OS in a univariate analysis and in a comparison with historical controls.
Dr. Daver and his colleagues concluded that azacitidine and nivolumab “produced an encouraging response rate and overall survival” in patients with relapsed/refractory AML.
“We believe that implementation of clinical and immune biomarkers to select patients are likely to yield further improved outcomes with these types of therapies in AML,” Dr. Daver said.
This research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Individual researchers also reported financial relationships with Bristol-Myers Squibb.
SOURCE: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.
FROM CANCER DISCOVERY
Key clinical point:
Major finding: The overall response rate was 33%.
Study details: This phase 2 trial included 70 patients with relapsed/refractory acute myeloid leukemia.
Disclosures: The research was supported by Bristol-Myers Squibb, the University of Texas MD Anderson Cancer Center, and the Dick Clark Immunotherapy Research Fund. Researchers reported financial relationships with Bristol-Myers Squibb.
Source: Daver N et al. Cancer Discov. 2018 Nov 8. doi: 10.1158/2159-8290.CD-18-0774.