Lymphoma & Plasma Cell Disorders

Image by Ed Uthman

The US Food and Drug Administration (FDA) has granted orphan drug designation to CPI-613 for the treatment of Burkitt lymphoma (BL).

CPI-613 is a novel lipoic acid analogue that inhibits multiple enzyme targets within the tricarboxylic acid cycle.

The drug is in development as a treatment for hematologic malignancies and solid tumors.

In a phase 1 trial of patients with advanced hematologic malignancies, CPI-613 produced a response in a patient with relapsed BL.

Now, Rafael Pharmaceuticals, Inc., the company developing CPI-613, is launching a phase 2 trial of the drug in patients with relapsed or refractory BL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6.

In the phase 1 trial, the patient with relapsed BL achieved a partial response to CPI-613 monotherapy and was ultimately cleared of disease after surgery.

The patient, a 19-year-old female, began taking CPI-613 (2940 mg/m²) after her second relapse. She achieved a radiographic partial response after the third cycle of CPI-613.

The patient completed 17 cycles of CPI-613 over 51 weeks. She decided to stop treatment after the 17th cycle to pursue a surgical resection of residual tumor. The pathology of the surgical specimen revealed BL with extensive necrosis.

Clinical follow-up on the patient showed no evidence of disease more than 36 months later. And CPI-613 was considered well tolerated in this patient.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Ed Uthman

The US Food and Drug Administration (FDA) has granted orphan drug designation to CPI-613 for the treatment of Burkitt lymphoma (BL).

CPI-613 is a novel lipoic acid analogue that inhibits multiple enzyme targets within the tricarboxylic acid cycle.

The drug is in development as a treatment for hematologic malignancies and solid tumors.

In a phase 1 trial of patients with advanced hematologic malignancies, CPI-613 produced a response in a patient with relapsed BL.

Now, Rafael Pharmaceuticals, Inc., the company developing CPI-613, is launching a phase 2 trial of the drug in patients with relapsed or refractory BL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6.

In the phase 1 trial, the patient with relapsed BL achieved a partial response to CPI-613 monotherapy and was ultimately cleared of disease after surgery.

The patient, a 19-year-old female, began taking CPI-613 (2940 mg/m²) after her second relapse. She achieved a radiographic partial response after the third cycle of CPI-613.

The patient completed 17 cycles of CPI-613 over 51 weeks. She decided to stop treatment after the 17th cycle to pursue a surgical resection of residual tumor. The pathology of the surgical specimen revealed BL with extensive necrosis.

Clinical follow-up on the patient showed no evidence of disease more than 36 months later. And CPI-613 was considered well tolerated in this patient.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Image by Ed Uthman

The US Food and Drug Administration (FDA) has granted orphan drug designation to CPI-613 for the treatment of Burkitt lymphoma (BL).

CPI-613 is a novel lipoic acid analogue that inhibits multiple enzyme targets within the tricarboxylic acid cycle.

The drug is in development as a treatment for hematologic malignancies and solid tumors.

In a phase 1 trial of patients with advanced hematologic malignancies, CPI-613 produced a response in a patient with relapsed BL.

Now, Rafael Pharmaceuticals, Inc., the company developing CPI-613, is launching a phase 2 trial of the drug in patients with relapsed or refractory BL and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6.

In the phase 1 trial, the patient with relapsed BL achieved a partial response to CPI-613 monotherapy and was ultimately cleared of disease after surgery.

The patient, a 19-year-old female, began taking CPI-613 (2940 mg/m²) after her second relapse. She achieved a radiographic partial response after the third cycle of CPI-613.

The patient completed 17 cycles of CPI-613 over 51 weeks. She decided to stop treatment after the 17th cycle to pursue a surgical resection of residual tumor. The pathology of the surgical specimen revealed BL with extensive necrosis.

Clinical follow-up on the patient showed no evidence of disease more than 36 months later. And CPI-613 was considered well tolerated in this patient.

About orphan designation

The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Photo by Bill Branson

A survey of more than 15,000 childhood cancer survivors (CCSs) revealed that many were unconcerned about their risk of health problems.

Thirty-one percent of CCSs said they were “not at all” or “not very” concerned about their future health, and 40% said they were “not at all” or “not very” concerned about developing new cancers.

Researchers say it isn’t clear what’s driving this lack of concern, but it is possible that some CCSs don’t know they have an increased risk of new malignancies and other health problems.

“Other possibilities include that some survivors may actually be aware of their increased risks and choose not to be concerned, or it may even be that some survivors are, indeed, following health guidelines and working with healthcare providers, leading to their lack of concern,” said Todd Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Gibson and his colleagues conducted this research and reported the results in Cancer.

The researchers analyzed data on 15,620 CCSs and 3991 of their siblings who did not have a history of cancer. The data came from questionnaires administered to participants in the Childhood Cancer Survivor Study.

At baseline, the median time from CCSs’ cancer diagnosis was 17 years (interquartile range [IQR], 14-21). Their median age at baseline was 26 (IQR, 22-31 years), and the siblings’ median age was 29 (IQR, 24-35).

When respondents were asked about their level of concern regarding their future health, the answers were as follows:

• 12% of both CCSs and siblings were “not at all concerned”
• 18.7% of CCSs and 21.6% of siblings were “not very concerned”
• 23.2% of CCSs and 24.1% of siblings were “concerned”
• 21.4% of CCSs and 22.2% of siblings were “somewhat concerned”
• 24.8% of CCSs and 20.1% of siblings were “very concerned.”

When respondents were asked to rate their level of concern about developing a new cancer, the answers were as follows:

• 17.2% of CCSs and 16.3% of siblings were “not at all concerned”
• 22.8% of CCSs and 22.2% of siblings were “not very concerned”
• 21.1% of CCSs and 25.1% of siblings were “concerned”
• 18.3% of CCSs and 18.4% of siblings were “somewhat concerned”
• 20.6% of CCSs and 18.1% of siblings were “very concerned.”

When the researchers adjusted for age, sex, race/ethnicity, education, and decade of diagnosis, CCSs were only slightly more likely than siblings to report concern about future health (relative risk, 1.12) or subsequent cancer (relative risk, 1.02).

“That similarity [between CCS and sibling answers] was really the major surprise in our findings,” Dr Gibson said. “Despite the fact that survivors have such a greatly increased risk of both second cancers and other health problems, their perception of risk was not always commensurate with their actual risk.”

The researchers did find that CCSs were more likely to report concern about future health or developing cancer if they were female, non-Hispanic black or Hispanic, older, identified as having clinical anxiety, or had already experienced a grade 3/4 chronic condition or subsequent cancer.

However, it isn’t clear why some CCSs are concerned about their future health and others are not.

“At this point, we can only speculate, but the most obvious reason [for lack of concern] would be that survivors may not fully understand their risks,” Dr Gibson said. “We do know from prior studies that not all survivors are fully aware of the specific treatments they received and how those might increase their risks of late effects.”

“If, however, survivors are aware but not motivated or sufficiently aroused to be concerned, then more motivational education will have to be developed. In any case, these findings offer a teaching point that we can use to emphasize to all survivors that they need to understand their risks.”

Photo by Bill Branson

A survey of more than 15,000 childhood cancer survivors (CCSs) revealed that many were unconcerned about their risk of health problems.

Thirty-one percent of CCSs said they were “not at all” or “not very” concerned about their future health, and 40% said they were “not at all” or “not very” concerned about developing new cancers.

Researchers say it isn’t clear what’s driving this lack of concern, but it is possible that some CCSs don’t know they have an increased risk of new malignancies and other health problems.

“Other possibilities include that some survivors may actually be aware of their increased risks and choose not to be concerned, or it may even be that some survivors are, indeed, following health guidelines and working with healthcare providers, leading to their lack of concern,” said Todd Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Gibson and his colleagues conducted this research and reported the results in Cancer.

The researchers analyzed data on 15,620 CCSs and 3991 of their siblings who did not have a history of cancer. The data came from questionnaires administered to participants in the Childhood Cancer Survivor Study.

At baseline, the median time from CCSs’ cancer diagnosis was 17 years (interquartile range [IQR], 14-21). Their median age at baseline was 26 (IQR, 22-31 years), and the siblings’ median age was 29 (IQR, 24-35).

When respondents were asked about their level of concern regarding their future health, the answers were as follows:

• 12% of both CCSs and siblings were “not at all concerned”
• 18.7% of CCSs and 21.6% of siblings were “not very concerned”
• 23.2% of CCSs and 24.1% of siblings were “concerned”
• 21.4% of CCSs and 22.2% of siblings were “somewhat concerned”
• 24.8% of CCSs and 20.1% of siblings were “very concerned.”

When respondents were asked to rate their level of concern about developing a new cancer, the answers were as follows:

• 17.2% of CCSs and 16.3% of siblings were “not at all concerned”
• 22.8% of CCSs and 22.2% of siblings were “not very concerned”
• 21.1% of CCSs and 25.1% of siblings were “concerned”
• 18.3% of CCSs and 18.4% of siblings were “somewhat concerned”
• 20.6% of CCSs and 18.1% of siblings were “very concerned.”

When the researchers adjusted for age, sex, race/ethnicity, education, and decade of diagnosis, CCSs were only slightly more likely than siblings to report concern about future health (relative risk, 1.12) or subsequent cancer (relative risk, 1.02).

“That similarity [between CCS and sibling answers] was really the major surprise in our findings,” Dr Gibson said. “Despite the fact that survivors have such a greatly increased risk of both second cancers and other health problems, their perception of risk was not always commensurate with their actual risk.”

The researchers did find that CCSs were more likely to report concern about future health or developing cancer if they were female, non-Hispanic black or Hispanic, older, identified as having clinical anxiety, or had already experienced a grade 3/4 chronic condition or subsequent cancer.

However, it isn’t clear why some CCSs are concerned about their future health and others are not.

“At this point, we can only speculate, but the most obvious reason [for lack of concern] would be that survivors may not fully understand their risks,” Dr Gibson said. “We do know from prior studies that not all survivors are fully aware of the specific treatments they received and how those might increase their risks of late effects.”

“If, however, survivors are aware but not motivated or sufficiently aroused to be concerned, then more motivational education will have to be developed. In any case, these findings offer a teaching point that we can use to emphasize to all survivors that they need to understand their risks.”

Photo by Bill Branson

A survey of more than 15,000 childhood cancer survivors (CCSs) revealed that many were unconcerned about their risk of health problems.

Thirty-one percent of CCSs said they were “not at all” or “not very” concerned about their future health, and 40% said they were “not at all” or “not very” concerned about developing new cancers.

Researchers say it isn’t clear what’s driving this lack of concern, but it is possible that some CCSs don’t know they have an increased risk of new malignancies and other health problems.

“Other possibilities include that some survivors may actually be aware of their increased risks and choose not to be concerned, or it may even be that some survivors are, indeed, following health guidelines and working with healthcare providers, leading to their lack of concern,” said Todd Gibson, PhD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

Dr Gibson and his colleagues conducted this research and reported the results in Cancer.

The researchers analyzed data on 15,620 CCSs and 3991 of their siblings who did not have a history of cancer. The data came from questionnaires administered to participants in the Childhood Cancer Survivor Study.

At baseline, the median time from CCSs’ cancer diagnosis was 17 years (interquartile range [IQR], 14-21). Their median age at baseline was 26 (IQR, 22-31 years), and the siblings’ median age was 29 (IQR, 24-35).

When respondents were asked about their level of concern regarding their future health, the answers were as follows:

• 12% of both CCSs and siblings were “not at all concerned”
• 18.7% of CCSs and 21.6% of siblings were “not very concerned”
• 23.2% of CCSs and 24.1% of siblings were “concerned”
• 21.4% of CCSs and 22.2% of siblings were “somewhat concerned”
• 24.8% of CCSs and 20.1% of siblings were “very concerned.”

When respondents were asked to rate their level of concern about developing a new cancer, the answers were as follows:

• 17.2% of CCSs and 16.3% of siblings were “not at all concerned”
• 22.8% of CCSs and 22.2% of siblings were “not very concerned”
• 21.1% of CCSs and 25.1% of siblings were “concerned”
• 18.3% of CCSs and 18.4% of siblings were “somewhat concerned”
• 20.6% of CCSs and 18.1% of siblings were “very concerned.”

When the researchers adjusted for age, sex, race/ethnicity, education, and decade of diagnosis, CCSs were only slightly more likely than siblings to report concern about future health (relative risk, 1.12) or subsequent cancer (relative risk, 1.02).

“That similarity [between CCS and sibling answers] was really the major surprise in our findings,” Dr Gibson said. “Despite the fact that survivors have such a greatly increased risk of both second cancers and other health problems, their perception of risk was not always commensurate with their actual risk.”

The researchers did find that CCSs were more likely to report concern about future health or developing cancer if they were female, non-Hispanic black or Hispanic, older, identified as having clinical anxiety, or had already experienced a grade 3/4 chronic condition or subsequent cancer.

However, it isn’t clear why some CCSs are concerned about their future health and others are not.

“At this point, we can only speculate, but the most obvious reason [for lack of concern] would be that survivors may not fully understand their risks,” Dr Gibson said. “We do know from prior studies that not all survivors are fully aware of the specific treatments they received and how those might increase their risks of late effects.”

“If, however, survivors are aware but not motivated or sufficiently aroused to be concerned, then more motivational education will have to be developed. In any case, these findings offer a teaching point that we can use to emphasize to all survivors that they need to understand their risks.”

CHICAGO – The CD19–directed chimeric antigen receptor (CAR) T-cell product lisocabtagene maraleucel (liso-cel, JCAR017) produced durable responses in poor-prognosis patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), follow-up results of a phase 1 trial show.

Nearly 90% of DLBCL patients who achieved complete response as their best response on liso-cel were alive at 1 year in the study, according to investigator Jeremy S. Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.

That result is “far superior to what we would have anticipated with conventional therapies in a largely chemorefractory DLBCL population,” Dr. Abramson said at the annual meeting of the American Society of Clinical Oncology.

The new data on liso-cel come on the heels of a second approval of a CAR T-cell therapy for DLBCL, noted Caron Jacobson, MD, of Dana-Farber Cancer Institute, Boston.

Axicabtagene ciloleucel (Yescarta) was approved in October 2017 by the U.S. Food and Drug Administration for relapsed or refractory large B-cell lymphomas, including DLBCL. In May 2018, tisagenlecleucel (Kymriah) received its second FDA approval to treat relapsed or refractory large B-cell lymphomas, including DLBCL.

CAR T-cell therapy “really has transformed outcomes for a group of patients who previously had no other standard of care and who… have a relatively short overall survival,” Dr. Jacobson said.

At the meeting, Dr. Abramson presented findings on DLBCL patients in TRANSCEND NHL 001, a phase 1, multicenter, open-label study of the CD-19 targeted CAR T-cell therapy in relapsed and refractory B-cell non-Hodgkin lymphoma.

About 90% of treated DLBCL patients had one or more poor-risk disease features, such as ECOG performance status 2 and primary refractory disease, which predict poor overall survival, according to Dr. Abramson.

Dr. Abramson’s presentation focused on 102 evaluable DLBCL patients in the dose-finding and dose-expansion cohorts of the TRANSCEND study, including a subset analysis of a core group of 73 patients who met the criteria for pivotal dose cohort of the study (1 x 10⁸ cells given as a single dose).

For the full set of 102 DLBCL patients, the best overall response rate was 75%, including a best complete remission rate of 55%, according to presented data. In the core group of 73 DLBCL patients, best overall response and complete remission rates were 80% and 59%, respectively.

Investigators saw “encouraging” durable response rates at 6 months and beyond in the core DLBCL population, according to Dr. Abramson. Of patients with a complete remission at 3 months, 88% remained in complete remission at the 6-month follow-up, and 93% of those in remission at the 6-month time point were in ongoing response at a median follow-up of 8 months.

Median overall survival had not been reached in either the full or core DLBCL cohorts with a median of 12 months follow-up, he added, noting that 90% of patients who achieved complete remission as their best response remained alive at 1 year.

In terms of adverse effects, liso-cel is showing a low and manageable toxicity profile, with very low rates of severe cytokine release syndrome (CRS) and neurotoxicity at 1% and 13%, respectively, Dr. Abramson reported.

“This anti-CD19 CAR T cell has remarkable efficacy in a group of highly refractory aggressive B-cell non-Hodgkin lymphoma patients,” said Dr. Jacobson, commenting on results of the DLBCL subset.

Based on the data presented, liso-cel is “clearly competitive” with the approved CAR T-cell therapies, though she advised caution in comparing across studies. “I don’t think that there will be a randomized study of all three agents, but I do think that we’ll start to get comparative data from single institution experiences that are using all three products,” she said.

The pivotal DLBCL cohort of TRANSCEND NHL 001 has completed accrual and results will be presented at a future meeting, Dr. Abramson said.

Dr. Abramson reported disclosures related to Celgene, Genentech/Roche, Gilead Sciences, Novartis, Seattle Genetics, and Millennium.

SOURCE: Abramson JS et al. ASCO 2018. Abstract 7505.

CHICAGO – The CD19–directed chimeric antigen receptor (CAR) T-cell product lisocabtagene maraleucel (liso-cel, JCAR017) produced durable responses in poor-prognosis patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), follow-up results of a phase 1 trial show.

Nearly 90% of DLBCL patients who achieved complete response as their best response on liso-cel were alive at 1 year in the study, according to investigator Jeremy S. Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.

That result is “far superior to what we would have anticipated with conventional therapies in a largely chemorefractory DLBCL population,” Dr. Abramson said at the annual meeting of the American Society of Clinical Oncology.

The new data on liso-cel come on the heels of a second approval of a CAR T-cell therapy for DLBCL, noted Caron Jacobson, MD, of Dana-Farber Cancer Institute, Boston.

Axicabtagene ciloleucel (Yescarta) was approved in October 2017 by the U.S. Food and Drug Administration for relapsed or refractory large B-cell lymphomas, including DLBCL. In May 2018, tisagenlecleucel (Kymriah) received its second FDA approval to treat relapsed or refractory large B-cell lymphomas, including DLBCL.

CAR T-cell therapy “really has transformed outcomes for a group of patients who previously had no other standard of care and who… have a relatively short overall survival,” Dr. Jacobson said.

At the meeting, Dr. Abramson presented findings on DLBCL patients in TRANSCEND NHL 001, a phase 1, multicenter, open-label study of the CD-19 targeted CAR T-cell therapy in relapsed and refractory B-cell non-Hodgkin lymphoma.

About 90% of treated DLBCL patients had one or more poor-risk disease features, such as ECOG performance status 2 and primary refractory disease, which predict poor overall survival, according to Dr. Abramson.

Dr. Abramson’s presentation focused on 102 evaluable DLBCL patients in the dose-finding and dose-expansion cohorts of the TRANSCEND study, including a subset analysis of a core group of 73 patients who met the criteria for pivotal dose cohort of the study (1 x 10⁸ cells given as a single dose).

For the full set of 102 DLBCL patients, the best overall response rate was 75%, including a best complete remission rate of 55%, according to presented data. In the core group of 73 DLBCL patients, best overall response and complete remission rates were 80% and 59%, respectively.

Investigators saw “encouraging” durable response rates at 6 months and beyond in the core DLBCL population, according to Dr. Abramson. Of patients with a complete remission at 3 months, 88% remained in complete remission at the 6-month follow-up, and 93% of those in remission at the 6-month time point were in ongoing response at a median follow-up of 8 months.

Median overall survival had not been reached in either the full or core DLBCL cohorts with a median of 12 months follow-up, he added, noting that 90% of patients who achieved complete remission as their best response remained alive at 1 year.

In terms of adverse effects, liso-cel is showing a low and manageable toxicity profile, with very low rates of severe cytokine release syndrome (CRS) and neurotoxicity at 1% and 13%, respectively, Dr. Abramson reported.

“This anti-CD19 CAR T cell has remarkable efficacy in a group of highly refractory aggressive B-cell non-Hodgkin lymphoma patients,” said Dr. Jacobson, commenting on results of the DLBCL subset.

Based on the data presented, liso-cel is “clearly competitive” with the approved CAR T-cell therapies, though she advised caution in comparing across studies. “I don’t think that there will be a randomized study of all three agents, but I do think that we’ll start to get comparative data from single institution experiences that are using all three products,” she said.

The pivotal DLBCL cohort of TRANSCEND NHL 001 has completed accrual and results will be presented at a future meeting, Dr. Abramson said.

Dr. Abramson reported disclosures related to Celgene, Genentech/Roche, Gilead Sciences, Novartis, Seattle Genetics, and Millennium.

SOURCE: Abramson JS et al. ASCO 2018. Abstract 7505.

CHICAGO – The CD19–directed chimeric antigen receptor (CAR) T-cell product lisocabtagene maraleucel (liso-cel, JCAR017) produced durable responses in poor-prognosis patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), follow-up results of a phase 1 trial show.

Nearly 90% of DLBCL patients who achieved complete response as their best response on liso-cel were alive at 1 year in the study, according to investigator Jeremy S. Abramson, MD, of Massachusetts General Hospital Cancer Center in Boston.

That result is “far superior to what we would have anticipated with conventional therapies in a largely chemorefractory DLBCL population,” Dr. Abramson said at the annual meeting of the American Society of Clinical Oncology.

The new data on liso-cel come on the heels of a second approval of a CAR T-cell therapy for DLBCL, noted Caron Jacobson, MD, of Dana-Farber Cancer Institute, Boston.

Axicabtagene ciloleucel (Yescarta) was approved in October 2017 by the U.S. Food and Drug Administration for relapsed or refractory large B-cell lymphomas, including DLBCL. In May 2018, tisagenlecleucel (Kymriah) received its second FDA approval to treat relapsed or refractory large B-cell lymphomas, including DLBCL.

CAR T-cell therapy “really has transformed outcomes for a group of patients who previously had no other standard of care and who… have a relatively short overall survival,” Dr. Jacobson said.

At the meeting, Dr. Abramson presented findings on DLBCL patients in TRANSCEND NHL 001, a phase 1, multicenter, open-label study of the CD-19 targeted CAR T-cell therapy in relapsed and refractory B-cell non-Hodgkin lymphoma.

About 90% of treated DLBCL patients had one or more poor-risk disease features, such as ECOG performance status 2 and primary refractory disease, which predict poor overall survival, according to Dr. Abramson.

Dr. Abramson’s presentation focused on 102 evaluable DLBCL patients in the dose-finding and dose-expansion cohorts of the TRANSCEND study, including a subset analysis of a core group of 73 patients who met the criteria for pivotal dose cohort of the study (1 x 10⁸ cells given as a single dose).

For the full set of 102 DLBCL patients, the best overall response rate was 75%, including a best complete remission rate of 55%, according to presented data. In the core group of 73 DLBCL patients, best overall response and complete remission rates were 80% and 59%, respectively.

Investigators saw “encouraging” durable response rates at 6 months and beyond in the core DLBCL population, according to Dr. Abramson. Of patients with a complete remission at 3 months, 88% remained in complete remission at the 6-month follow-up, and 93% of those in remission at the 6-month time point were in ongoing response at a median follow-up of 8 months.

Median overall survival had not been reached in either the full or core DLBCL cohorts with a median of 12 months follow-up, he added, noting that 90% of patients who achieved complete remission as their best response remained alive at 1 year.

In terms of adverse effects, liso-cel is showing a low and manageable toxicity profile, with very low rates of severe cytokine release syndrome (CRS) and neurotoxicity at 1% and 13%, respectively, Dr. Abramson reported.

“This anti-CD19 CAR T cell has remarkable efficacy in a group of highly refractory aggressive B-cell non-Hodgkin lymphoma patients,” said Dr. Jacobson, commenting on results of the DLBCL subset.

Based on the data presented, liso-cel is “clearly competitive” with the approved CAR T-cell therapies, though she advised caution in comparing across studies. “I don’t think that there will be a randomized study of all three agents, but I do think that we’ll start to get comparative data from single institution experiences that are using all three products,” she said.

The pivotal DLBCL cohort of TRANSCEND NHL 001 has completed accrual and results will be presented at a future meeting, Dr. Abramson said.

Dr. Abramson reported disclosures related to Celgene, Genentech/Roche, Gilead Sciences, Novartis, Seattle Genetics, and Millennium.

SOURCE: Abramson JS et al. ASCO 2018. Abstract 7505.

Ibrutinib in combination with rituximab as a treatment for Waldenström macroglobulinemia (WM) is under priority review by the Food and Drug Administration.

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is already approved as a single agent for WM. The addition of rituximab to the indication is based on positive results from the phase 3 INNOVATE study. In particular, the trial showed a superior progression-free survival rate at 30 months for the ibrutinib-rituximab combination at 82%, compared with placebo plus rituximab at 28% (N Engl J Med. 2018;378:2399-410).

The study’s lead investigator, Meletios A. Dimopoulos, MD, called the combination a “new standard of care” for WM at the recent annual meeting of the American Society of Clinical Oncology.

Ibrutinib, marketed as Imbruvica, is jointly developed and commercialized by Pharmacyclics and Janssen Biotech.

mschneider@mdedge.com

Ibrutinib in combination with rituximab as a treatment for Waldenström macroglobulinemia (WM) is under priority review by the Food and Drug Administration.

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is already approved as a single agent for WM. The addition of rituximab to the indication is based on positive results from the phase 3 INNOVATE study. In particular, the trial showed a superior progression-free survival rate at 30 months for the ibrutinib-rituximab combination at 82%, compared with placebo plus rituximab at 28% (N Engl J Med. 2018;378:2399-410).

The study’s lead investigator, Meletios A. Dimopoulos, MD, called the combination a “new standard of care” for WM at the recent annual meeting of the American Society of Clinical Oncology.

Ibrutinib, marketed as Imbruvica, is jointly developed and commercialized by Pharmacyclics and Janssen Biotech.

mschneider@mdedge.com

Ibrutinib in combination with rituximab as a treatment for Waldenström macroglobulinemia (WM) is under priority review by the Food and Drug Administration.

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is already approved as a single agent for WM. The addition of rituximab to the indication is based on positive results from the phase 3 INNOVATE study. In particular, the trial showed a superior progression-free survival rate at 30 months for the ibrutinib-rituximab combination at 82%, compared with placebo plus rituximab at 28% (N Engl J Med. 2018;378:2399-410).

The study’s lead investigator, Meletios A. Dimopoulos, MD, called the combination a “new standard of care” for WM at the recent annual meeting of the American Society of Clinical Oncology.

Ibrutinib, marketed as Imbruvica, is jointly developed and commercialized by Pharmacyclics and Janssen Biotech.

mschneider@mdedge.com

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for ibrutinib (Imbruvica®) to be used in combination with rituximab in patients with Waldenström’s macroglobulinemia (WM).

The FDA intends to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Ibrutinib is already FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, previously treated mantle cell lymphoma, previously treated marginal zone lymphoma, previously treated chronic graft-versus-host disease, and WM.

If the new sNDA is approved, the use of ibrutinib in WM will extend beyond its current approved use as a single agent.

Phase 3 trial

The sNDA for ibrutinib and rituximab in WM is supported by data from the phase 3 iNNOVATE study. Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 8003) and were simultaneously published in NEJM.

iNNOVATE is a placebo-controlled, double-blind, phase 3 study that enrolled 150 patients with relapsed/refractory and treatment-naïve WM.

All patients received rituximab at 375 mg/m² with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.

Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.

The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.

The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).

The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm.

Serious AEs occurred in 43% and 33% of patients, respectively. There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.

Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).

AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for ibrutinib (Imbruvica®) to be used in combination with rituximab in patients with Waldenström’s macroglobulinemia (WM).

The FDA intends to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Ibrutinib is already FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, previously treated mantle cell lymphoma, previously treated marginal zone lymphoma, previously treated chronic graft-versus-host disease, and WM.

If the new sNDA is approved, the use of ibrutinib in WM will extend beyond its current approved use as a single agent.

Phase 3 trial

The sNDA for ibrutinib and rituximab in WM is supported by data from the phase 3 iNNOVATE study. Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 8003) and were simultaneously published in NEJM.

iNNOVATE is a placebo-controlled, double-blind, phase 3 study that enrolled 150 patients with relapsed/refractory and treatment-naïve WM.

All patients received rituximab at 375 mg/m² with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.

Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.

The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.

The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).

The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm.

Serious AEs occurred in 43% and 33% of patients, respectively. There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.

Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).

AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).

Photo courtesy of Janssen

The US Food and Drug Administration (FDA) has accepted for priority review a supplemental new drug application (sNDA) for ibrutinib (Imbruvica®) to be used in combination with rituximab in patients with Waldenström’s macroglobulinemia (WM).

The FDA intends to take action on a priority review application within 6 months of receiving it, rather than the standard 10 months.

The FDA grants priority review to applications for products that may provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

Ibrutinib is a first-in-class Bruton’s tyrosine kinase inhibitor jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Ibrutinib is already FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, previously treated mantle cell lymphoma, previously treated marginal zone lymphoma, previously treated chronic graft-versus-host disease, and WM.

If the new sNDA is approved, the use of ibrutinib in WM will extend beyond its current approved use as a single agent.

Phase 3 trial

The sNDA for ibrutinib and rituximab in WM is supported by data from the phase 3 iNNOVATE study. Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 8003) and were simultaneously published in NEJM.

iNNOVATE is a placebo-controlled, double-blind, phase 3 study that enrolled 150 patients with relapsed/refractory and treatment-naïve WM.

All patients received rituximab at 375 mg/m² with weekly infusions at weeks 1 to 4 and 17 to 20. They also received either ibrutinib (420 mg) or placebo once daily continuously until criteria for permanent discontinuation were met.

Overall response rates were significantly higher in the ibrutinib arm than the placebo arm—92% and 47%, respectively (P<0.0001). Complete response rates were 3% and 1%, respectively.

The median time to next treatment was not reached for the ibrutinib arm and was 18 months for the placebo arm (hazard ratio=0.096; P<0.0001). Of the patients randomized to ibrutinib plus rituximab, 75% continued on treatment at last follow-up.

The 30-month progression-free survival rates were 82% in the ibrutinib arm and 28% in the placebo arm. The median progression-free survival was not reached in the ibrutinib arm and was 20.3 months in the placebo arm (hazard ratio=0.20; P<0.0001).

The 30-month overall survival rates were 94% in the ibrutinib arm and 92% in the placebo arm.

Grade 3 or higher treatment-emergent adverse events (AEs) occurred in 60% of patients in the ibrutinib arm and 61% in the placebo arm.

Serious AEs occurred in 43% and 33% of patients, respectively. There were no fatal AEs in the ibrutinib arm and 3 in the rituximab arm.

Grade 3 or higher AEs that occurred more frequently in the ibrutinib arm than the placebo arm included atrial fibrillation (12% vs 1%) and hypertension (13% vs 4%).

AEs that occurred less frequently in the ibrutinib arm than the placebo arm included grade 3 or higher infusion reactions (1% vs 16%) and any-grade IgM flare (8% vs 47%).

©ASCO/Scott Morgan 2018

CHICAGO—A novel CD19-targeted T-cell therapy induced complete metabolic responses (CMRs) and no cytokine release syndrome (CRS) in patients with B-cell lymphomas in a first-in-human clinical study.

All subjects achieving CMR at the 1-month safety and efficacy assessment continued to show CMR at 3 months, investigators reported at the 2018 ASCO Annual Meeting (abstract 3049*).

The therapy is built on a novel platform, ARTEMIS, designed to match the potency of chimeric antigen receptor (CAR) T-cell therapy but trigger less cytokine release when the target is engaged, investigators explained.

That platform is “potentially a major improvement” over existing CAR-T cell therapy, said Zhi Tao Ying, MD, of Peking University Cancer Hospital & Institute in Beijing, China, and coauthors in a poster presented at ASCO.

The treatment, called ET190L1-ARTEMIS, utilizes the T-cell receptor platform and a proprietary human anti-CD19 antibody to target CD19-positive malignancies.

The investigators reported on 21 adults with CD-19 positive relapsed and refractory B-cell lymphomas who had received a median of 4 lines of previous therapy.

Patients received autologous ET190L1-ARTEMIS T cells in 1 of 3 dosing cohorts: 3 patients at 1 x 10⁶/kg, 13 at 3 x 10⁶/kg, and 5 at 6 x 10⁶/kg.

Of 17 patients completing a first-month efficacy assessment, 11 (65%) responded, including 7 CMRs and 3 partial responses. One patient had stable disease.

Seven of the 11 responders completed a third-month efficacy assessment, as of this analysis. Of 5 patients with CMR at month 1, all 5 maintained CMR at month 3. Likewise, 1 patient in partial response and 1 with stable disease at month 1 had the same response status at month 3.

There were no cases of CRS or neurotoxicity in 17 patients who completed the 1-month safety and efficacy assessment reported at ASCO. Grade 3 or greater adverse events in those subjects included lymphopenia in 17 (100%) and neutropenia in 5 (29%).

Eureka Therapeutics Inc., of Emeryville, California, is developing ET190L1-ARTEMIS. Co-investigators in this trial were from Eureka, Xi-An Jiaotong University in China, and Duke University School of Medicine in Durham, North Carolina.

A phase 1 trial of ET190L1-ARTEMIS in patients with relapsed and refractory non-Hodgkin lymphoma has been initiated at Duke University, and  investigators say another US phase 1 trial including relapsed and refractory pediatric acute lymphoblastic leukemia patients will begin later this year. 

Data in the abstract differ from that presented in the poster.

©ASCO/Scott Morgan 2018

CHICAGO—A novel CD19-targeted T-cell therapy induced complete metabolic responses (CMRs) and no cytokine release syndrome (CRS) in patients with B-cell lymphomas in a first-in-human clinical study.

All subjects achieving CMR at the 1-month safety and efficacy assessment continued to show CMR at 3 months, investigators reported at the 2018 ASCO Annual Meeting (abstract 3049*).

The therapy is built on a novel platform, ARTEMIS, designed to match the potency of chimeric antigen receptor (CAR) T-cell therapy but trigger less cytokine release when the target is engaged, investigators explained.

That platform is “potentially a major improvement” over existing CAR-T cell therapy, said Zhi Tao Ying, MD, of Peking University Cancer Hospital & Institute in Beijing, China, and coauthors in a poster presented at ASCO.

The treatment, called ET190L1-ARTEMIS, utilizes the T-cell receptor platform and a proprietary human anti-CD19 antibody to target CD19-positive malignancies.

The investigators reported on 21 adults with CD-19 positive relapsed and refractory B-cell lymphomas who had received a median of 4 lines of previous therapy.

Patients received autologous ET190L1-ARTEMIS T cells in 1 of 3 dosing cohorts: 3 patients at 1 x 10⁶/kg, 13 at 3 x 10⁶/kg, and 5 at 6 x 10⁶/kg.

Of 17 patients completing a first-month efficacy assessment, 11 (65%) responded, including 7 CMRs and 3 partial responses. One patient had stable disease.

Seven of the 11 responders completed a third-month efficacy assessment, as of this analysis. Of 5 patients with CMR at month 1, all 5 maintained CMR at month 3. Likewise, 1 patient in partial response and 1 with stable disease at month 1 had the same response status at month 3.

There were no cases of CRS or neurotoxicity in 17 patients who completed the 1-month safety and efficacy assessment reported at ASCO. Grade 3 or greater adverse events in those subjects included lymphopenia in 17 (100%) and neutropenia in 5 (29%).

Eureka Therapeutics Inc., of Emeryville, California, is developing ET190L1-ARTEMIS. Co-investigators in this trial were from Eureka, Xi-An Jiaotong University in China, and Duke University School of Medicine in Durham, North Carolina.

A phase 1 trial of ET190L1-ARTEMIS in patients with relapsed and refractory non-Hodgkin lymphoma has been initiated at Duke University, and  investigators say another US phase 1 trial including relapsed and refractory pediatric acute lymphoblastic leukemia patients will begin later this year. 

Data in the abstract differ from that presented in the poster.

©ASCO/Scott Morgan 2018

CHICAGO—A novel CD19-targeted T-cell therapy induced complete metabolic responses (CMRs) and no cytokine release syndrome (CRS) in patients with B-cell lymphomas in a first-in-human clinical study.

All subjects achieving CMR at the 1-month safety and efficacy assessment continued to show CMR at 3 months, investigators reported at the 2018 ASCO Annual Meeting (abstract 3049*).

The therapy is built on a novel platform, ARTEMIS, designed to match the potency of chimeric antigen receptor (CAR) T-cell therapy but trigger less cytokine release when the target is engaged, investigators explained.

That platform is “potentially a major improvement” over existing CAR-T cell therapy, said Zhi Tao Ying, MD, of Peking University Cancer Hospital & Institute in Beijing, China, and coauthors in a poster presented at ASCO.

The treatment, called ET190L1-ARTEMIS, utilizes the T-cell receptor platform and a proprietary human anti-CD19 antibody to target CD19-positive malignancies.

The investigators reported on 21 adults with CD-19 positive relapsed and refractory B-cell lymphomas who had received a median of 4 lines of previous therapy.

Patients received autologous ET190L1-ARTEMIS T cells in 1 of 3 dosing cohorts: 3 patients at 1 x 10⁶/kg, 13 at 3 x 10⁶/kg, and 5 at 6 x 10⁶/kg.

Of 17 patients completing a first-month efficacy assessment, 11 (65%) responded, including 7 CMRs and 3 partial responses. One patient had stable disease.

Seven of the 11 responders completed a third-month efficacy assessment, as of this analysis. Of 5 patients with CMR at month 1, all 5 maintained CMR at month 3. Likewise, 1 patient in partial response and 1 with stable disease at month 1 had the same response status at month 3.

There were no cases of CRS or neurotoxicity in 17 patients who completed the 1-month safety and efficacy assessment reported at ASCO. Grade 3 or greater adverse events in those subjects included lymphopenia in 17 (100%) and neutropenia in 5 (29%).

Eureka Therapeutics Inc., of Emeryville, California, is developing ET190L1-ARTEMIS. Co-investigators in this trial were from Eureka, Xi-An Jiaotong University in China, and Duke University School of Medicine in Durham, North Carolina.

A phase 1 trial of ET190L1-ARTEMIS in patients with relapsed and refractory non-Hodgkin lymphoma has been initiated at Duke University, and  investigators say another US phase 1 trial including relapsed and refractory pediatric acute lymphoblastic leukemia patients will begin later this year. 

Data in the abstract differ from that presented in the poster.

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, according to Carl June, MD, the Richard W Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia. That approval is anticipated sometime in 2019, and will “completely transform oncology,” Dr June said in a recent interview. “Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells.”

Researcher-turned-patient

The first treated patient in a trial of a novel anti–B-cell maturation antigen (BCMA)–specific CAR T-cell therapy (CART-BCMA)¹ developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset. Earlier this year, Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, outed himself as that first patient when he announced that CART-BCMA saved his life.²

Dr Wright had been diagnosed with multiple myeloma about 12 years ago and had failed 11 previous chemotherapies before he was enrolled in the CART-BCMA trial. He remains cancer free more than 2 years after receiving CART-BCMA and he’s now conducting CAR T-cell–related research in his UT Southwestern laboratory to broaden the effectiveness of current CAR T-cell therapies. In particular, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, because most patients who fail CAR T-cell therapy are elderly and might have terminally short telomeres. ²

Pharma lines up the trials

An ongoing University of Pennsylvania trial led by Adam D Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the 2016 annual meeting of the American Society of Hematology (ASH).³ In addition, multiple companies are pursuing registration trials for CAR T-cell therapies in myeloma, Dr June said.

Among those companies are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. The product was granted breakthrough therapy designation by the US Food and Drug Administration in November 2017 and will thus receive expedited review by the agency. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial.⁴ Updated findings from that trial were presented at the 2017 ASH annual meeting and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.⁵

Janssen Biotech Inc and Legend Biotech USA Inc/ Legend Biotech Ireland Ltd have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr June said. The companies announced in late 2017 that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate, LCAR-B38M.⁶ It has been accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
 

Cost, financial toxicity, and a new therapeutic landscape

The rush for the approval of a CAR T-cell therapy for myeloma will lead to a welcome addition to the treatment armamentarium not just because of the clinical benefits, but because of the possibility of reducing disease-related costs (p. e177). Although myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr June noted, and since many patients live with their disease for a long time, that can mean substantial “financial toxicity” being associated with treatment for the disease. “So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added.

Dr June explained that tisagenlecleucel, the first CAR T-cell therapy to be approved (in August 2017; p. e126), was for pediatric acute lymphoblastic leukemia that had relapsed at least twice.⁷ “That’s only about 600 kids a year in the United States, so it’s an ultra-orphan market,” he said. However, with the subsequent October 2017 approval of axicabtagene ciloleucel for certain cases of large B-cell lymphoma⁸ and the anticipated myeloma approval, CAR T-cell therapy will move away from that orphan status.

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s, when many voiced concern about the new therapy because it was available at only 2 centers in the United states and required a high level of specialized skill. “But over the years, millions of transplants have been done [and] they’re done at many community centers. And it’s the same thing with CARs.” There are now 30 centers offering CAR T-cell therapy and people have to be trained. “It’s a new skill set, and it will take time,” he said.
 

Access to trials: balancing demand and availability

That delay can be particularly frustrating because there are many patients who might benefit “in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr June noted.

“There’s more demand than availability, and it’s going to take a while” for that to change, he said. The solution most likely will involve the complementary use of off-the-shelf CAR T cells in some patients to induce remission and perhaps provide a bridge to another definitive therapy, and ultrapersonalized CAR T-cell therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

CRISPR-Cas9 gene editing is also being considered as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute-funded NYCE study,⁹ Dr June said. “We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial.”

Disclosures. Dr June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, according to Carl June, MD, the Richard W Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia. That approval is anticipated sometime in 2019, and will “completely transform oncology,” Dr June said in a recent interview. “Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells.”

Researcher-turned-patient

The first treated patient in a trial of a novel anti–B-cell maturation antigen (BCMA)–specific CAR T-cell therapy (CART-BCMA)¹ developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset. Earlier this year, Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, outed himself as that first patient when he announced that CART-BCMA saved his life.²

Dr Wright had been diagnosed with multiple myeloma about 12 years ago and had failed 11 previous chemotherapies before he was enrolled in the CART-BCMA trial. He remains cancer free more than 2 years after receiving CART-BCMA and he’s now conducting CAR T-cell–related research in his UT Southwestern laboratory to broaden the effectiveness of current CAR T-cell therapies. In particular, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, because most patients who fail CAR T-cell therapy are elderly and might have terminally short telomeres. ²

Pharma lines up the trials

An ongoing University of Pennsylvania trial led by Adam D Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the 2016 annual meeting of the American Society of Hematology (ASH).³ In addition, multiple companies are pursuing registration trials for CAR T-cell therapies in myeloma, Dr June said.

Among those companies are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. The product was granted breakthrough therapy designation by the US Food and Drug Administration in November 2017 and will thus receive expedited review by the agency. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial.⁴ Updated findings from that trial were presented at the 2017 ASH annual meeting and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.⁵

Janssen Biotech Inc and Legend Biotech USA Inc/ Legend Biotech Ireland Ltd have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr June said. The companies announced in late 2017 that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate, LCAR-B38M.⁶ It has been accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
 

Cost, financial toxicity, and a new therapeutic landscape

The rush for the approval of a CAR T-cell therapy for myeloma will lead to a welcome addition to the treatment armamentarium not just because of the clinical benefits, but because of the possibility of reducing disease-related costs (p. e177). Although myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr June noted, and since many patients live with their disease for a long time, that can mean substantial “financial toxicity” being associated with treatment for the disease. “So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added.

Dr June explained that tisagenlecleucel, the first CAR T-cell therapy to be approved (in August 2017; p. e126), was for pediatric acute lymphoblastic leukemia that had relapsed at least twice.⁷ “That’s only about 600 kids a year in the United States, so it’s an ultra-orphan market,” he said. However, with the subsequent October 2017 approval of axicabtagene ciloleucel for certain cases of large B-cell lymphoma⁸ and the anticipated myeloma approval, CAR T-cell therapy will move away from that orphan status.

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s, when many voiced concern about the new therapy because it was available at only 2 centers in the United states and required a high level of specialized skill. “But over the years, millions of transplants have been done [and] they’re done at many community centers. And it’s the same thing with CARs.” There are now 30 centers offering CAR T-cell therapy and people have to be trained. “It’s a new skill set, and it will take time,” he said.
 

Access to trials: balancing demand and availability

That delay can be particularly frustrating because there are many patients who might benefit “in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr June noted.

“There’s more demand than availability, and it’s going to take a while” for that to change, he said. The solution most likely will involve the complementary use of off-the-shelf CAR T cells in some patients to induce remission and perhaps provide a bridge to another definitive therapy, and ultrapersonalized CAR T-cell therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

CRISPR-Cas9 gene editing is also being considered as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute-funded NYCE study,⁹ Dr June said. “We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial.”

Disclosures. Dr June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

The next major approval in the chimeric antigen receptor (CAR) T-cell therapy arena will target multiple myeloma, according to Carl June, MD, the Richard W Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia. That approval is anticipated sometime in 2019, and will “completely transform oncology,” Dr June said in a recent interview. “Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells.”

Researcher-turned-patient

The first treated patient in a trial of a novel anti–B-cell maturation antigen (BCMA)–specific CAR T-cell therapy (CART-BCMA)¹ developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset. Earlier this year, Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas (UT) Southwestern Medical Center in Dallas, outed himself as that first patient when he announced that CART-BCMA saved his life.²

Dr Wright had been diagnosed with multiple myeloma about 12 years ago and had failed 11 previous chemotherapies before he was enrolled in the CART-BCMA trial. He remains cancer free more than 2 years after receiving CART-BCMA and he’s now conducting CAR T-cell–related research in his UT Southwestern laboratory to broaden the effectiveness of current CAR T-cell therapies. In particular, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, because most patients who fail CAR T-cell therapy are elderly and might have terminally short telomeres. ²

Pharma lines up the trials

An ongoing University of Pennsylvania trial led by Adam D Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the 2016 annual meeting of the American Society of Hematology (ASH).³ In addition, multiple companies are pursuing registration trials for CAR T-cell therapies in myeloma, Dr June said.

Among those companies are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. The product was granted breakthrough therapy designation by the US Food and Drug Administration in November 2017 and will thus receive expedited review by the agency. It has also been fast-tracked in Europe.

The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial.⁴ Updated findings from that trial were presented at the 2017 ASH annual meeting and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 10⁶ CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.

Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 10⁶ CAR+ T cells.⁵

Janssen Biotech Inc and Legend Biotech USA Inc/ Legend Biotech Ireland Ltd have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr June said. The companies announced in late 2017 that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate, LCAR-B38M.⁶ It has been accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
 

Cost, financial toxicity, and a new therapeutic landscape

The rush for the approval of a CAR T-cell therapy for myeloma will lead to a welcome addition to the treatment armamentarium not just because of the clinical benefits, but because of the possibility of reducing disease-related costs (p. e177). Although myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr June noted, and since many patients live with their disease for a long time, that can mean substantial “financial toxicity” being associated with treatment for the disease. “So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added.

Dr June explained that tisagenlecleucel, the first CAR T-cell therapy to be approved (in August 2017; p. e126), was for pediatric acute lymphoblastic leukemia that had relapsed at least twice.⁷ “That’s only about 600 kids a year in the United States, so it’s an ultra-orphan market,” he said. However, with the subsequent October 2017 approval of axicabtagene ciloleucel for certain cases of large B-cell lymphoma⁸ and the anticipated myeloma approval, CAR T-cell therapy will move away from that orphan status.

“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s, when many voiced concern about the new therapy because it was available at only 2 centers in the United states and required a high level of specialized skill. “But over the years, millions of transplants have been done [and] they’re done at many community centers. And it’s the same thing with CARs.” There are now 30 centers offering CAR T-cell therapy and people have to be trained. “It’s a new skill set, and it will take time,” he said.
 

Access to trials: balancing demand and availability

That delay can be particularly frustrating because there are many patients who might benefit “in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr June noted.

“There’s more demand than availability, and it’s going to take a while” for that to change, he said. The solution most likely will involve the complementary use of off-the-shelf CAR T cells in some patients to induce remission and perhaps provide a bridge to another definitive therapy, and ultrapersonalized CAR T-cell therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.

CRISPR-Cas9 gene editing is also being considered as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute-funded NYCE study,⁹ Dr June said. “We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial.”

Disclosures. Dr June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.

Poster session at the 23rd Congress of the European Hematology Association

STOCKHOLM—The dual SYK/JAK inhibitor cerdulatinib has demonstrated efficacy in a phase 2 trial of patients with heavily pretreated B- and T-cell non-Hodgkin lymphomas (NHLs).

There were a few deaths due to sepsis or septic shock that were considered related to cerdulatinib, but investigators have taken steps to prevent additional deaths.

Cerdulatinib produced responses in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and other NHLs.

The 5 deaths due to sepsis or septic shock (3 concomitant with pneumonia) occurred early on in the trial, and dose reductions, monitoring, and antibiotic prophylaxis appeared to be effective in preventing additional deaths.

Results from this trial were presented in a poster (abstract PF437) at the 23rd Congress of the European Hematology Association (EHA).

The research was sponsored by Portola Pharmaceuticals, Inc.

The trial enrolled 114 patients. They had FL (grade 1-3A; n=39), PTCL (n=25), CTCL (n=5), CLL/SLL (n=28), other indolent NHLs (Waldenstrom’s macroglobulinemia and marginal zone lymphoma; n=12), or aggressive NHL (defined as diffuse large B-cell lymphoma [DLBCL], grade 3B FL, mantle cell lymphoma, and transformed NHL with relapsed disease; n=5).

The patients’ median age was 68 (range, 34-93), and 59% were male. The median number of prior treatment regimens was 3 (range, 1-13), and 37% of patients had refractory disease.

Patients received cerdulatinib at 25, 30, or 35 mg twice daily (BID). A total of 101 patients were evaluable as of May 4, 2018.

Response

The objective response rate (ORR) was 47% in the entire population. Thirteen patients achieved a complete response (CR), and 34 had a partial response (PR). Thirty-four patients remained on cerdulatinib at the data cut-off.

The ORR was 46% in the FL patients, with 3 patients achieving a CR and 13 achieving a PR. Thirteen FL patients remained on cerdulatinib.

In the CLL/SLL patients, the ORR was 61%. Two patients had a CR, and 15 had a PR. Four CLL/SLL patients remained on cerdulatinib.

In PTCL, the ORR was 35%. All 7 responders had a CR. Eleven PTCL patients remained on cerdulatinib.

Only 1 CTCL patient was evaluable, but this patient achieved a CR and remained on cerdulatinib.

The ORR was 42% for patients with other indolent NHLs, with 5 PRs and no CRs. Only 1 patient in this group remained on cerdulatinib.

For aggressive NHL, the ORR was 20%, with 1 PR and no CRs. None of the patients in this group stayed on cerdulatinib.

“Cerdulatinib continues to demonstrate promising results across a wide range of B- and T-cell malignancies, including early indications of the potential for durable responses,” said study investigator Paul Hamlin, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“The new signals in relapsed/refractory PTCL and CTCL are particularly compelling when you consider the limited treatment options for patients that fail frontline therapy.”

Safety

Grade 3 or higher adverse events included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).

The 5 deaths due to sepsis or septic shock (3 of which were concomitant with pneumonia) were considered related to cerdulatinib. Three of the deaths occurred in patients with CLL, 1 in a DLBCL patient, and 1 in an FL patient.

“One of the things we have seen [with CLL patients] is the background infection rate is quite a bit higher,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development at Portola Pharmaceuticals.

“You see this with multiple other agents, so we were not particularly surprised to see [sepsis/septic shock in CLL].”

Dr Curnutte noted that grade 5 sepsis/septic shock tended to occur in patients who were pre-colonized and/or had high plasma levels of cerdulatinib.

So, to prevent these adverse events, the starting dose of cerdulatinib was lowered, investigators began monitoring patients’ plasma levels, and all patients began receiving antibiotic prophylaxis. (Previously, only CLL patients had received this prophylaxis.)

The investigators found that lowering the starting dose from 35 mg BID to 30 mg or even 25 mg BID reduced plasma levels.

“At the 35 mg dose, 1 out of every 4 patients showed accumulation of the drug,” Dr Curnutte said. “In general, the use of the 30 mg BID or step-down 25 mg BID did not result in accumulation of drug.”

Dr Curnutte also noted that enrollment of CLL/SLL patients is complete, and investigators would be “very careful” if the study were to be re-opened to these patients.

For now, Portola is focused on completing enrollment in other patient groups on this phase 2 trial. The company is also hoping to conduct a phase 3 trial of cerdulatinib in PTCL that could begin as early as the end of this year.

Poster session at the 23rd Congress of the European Hematology Association

STOCKHOLM—The dual SYK/JAK inhibitor cerdulatinib has demonstrated efficacy in a phase 2 trial of patients with heavily pretreated B- and T-cell non-Hodgkin lymphomas (NHLs).

There were a few deaths due to sepsis or septic shock that were considered related to cerdulatinib, but investigators have taken steps to prevent additional deaths.

Cerdulatinib produced responses in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and other NHLs.

The 5 deaths due to sepsis or septic shock (3 concomitant with pneumonia) occurred early on in the trial, and dose reductions, monitoring, and antibiotic prophylaxis appeared to be effective in preventing additional deaths.

Results from this trial were presented in a poster (abstract PF437) at the 23rd Congress of the European Hematology Association (EHA).

The research was sponsored by Portola Pharmaceuticals, Inc.

The trial enrolled 114 patients. They had FL (grade 1-3A; n=39), PTCL (n=25), CTCL (n=5), CLL/SLL (n=28), other indolent NHLs (Waldenstrom’s macroglobulinemia and marginal zone lymphoma; n=12), or aggressive NHL (defined as diffuse large B-cell lymphoma [DLBCL], grade 3B FL, mantle cell lymphoma, and transformed NHL with relapsed disease; n=5).

The patients’ median age was 68 (range, 34-93), and 59% were male. The median number of prior treatment regimens was 3 (range, 1-13), and 37% of patients had refractory disease.

Patients received cerdulatinib at 25, 30, or 35 mg twice daily (BID). A total of 101 patients were evaluable as of May 4, 2018.

Response

The objective response rate (ORR) was 47% in the entire population. Thirteen patients achieved a complete response (CR), and 34 had a partial response (PR). Thirty-four patients remained on cerdulatinib at the data cut-off.

The ORR was 46% in the FL patients, with 3 patients achieving a CR and 13 achieving a PR. Thirteen FL patients remained on cerdulatinib.

In the CLL/SLL patients, the ORR was 61%. Two patients had a CR, and 15 had a PR. Four CLL/SLL patients remained on cerdulatinib.

In PTCL, the ORR was 35%. All 7 responders had a CR. Eleven PTCL patients remained on cerdulatinib.

Only 1 CTCL patient was evaluable, but this patient achieved a CR and remained on cerdulatinib.

The ORR was 42% for patients with other indolent NHLs, with 5 PRs and no CRs. Only 1 patient in this group remained on cerdulatinib.

For aggressive NHL, the ORR was 20%, with 1 PR and no CRs. None of the patients in this group stayed on cerdulatinib.

“Cerdulatinib continues to demonstrate promising results across a wide range of B- and T-cell malignancies, including early indications of the potential for durable responses,” said study investigator Paul Hamlin, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“The new signals in relapsed/refractory PTCL and CTCL are particularly compelling when you consider the limited treatment options for patients that fail frontline therapy.”

Safety

Grade 3 or higher adverse events included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).

The 5 deaths due to sepsis or septic shock (3 of which were concomitant with pneumonia) were considered related to cerdulatinib. Three of the deaths occurred in patients with CLL, 1 in a DLBCL patient, and 1 in an FL patient.

“One of the things we have seen [with CLL patients] is the background infection rate is quite a bit higher,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development at Portola Pharmaceuticals.

“You see this with multiple other agents, so we were not particularly surprised to see [sepsis/septic shock in CLL].”

Dr Curnutte noted that grade 5 sepsis/septic shock tended to occur in patients who were pre-colonized and/or had high plasma levels of cerdulatinib.

So, to prevent these adverse events, the starting dose of cerdulatinib was lowered, investigators began monitoring patients’ plasma levels, and all patients began receiving antibiotic prophylaxis. (Previously, only CLL patients had received this prophylaxis.)

The investigators found that lowering the starting dose from 35 mg BID to 30 mg or even 25 mg BID reduced plasma levels.

“At the 35 mg dose, 1 out of every 4 patients showed accumulation of the drug,” Dr Curnutte said. “In general, the use of the 30 mg BID or step-down 25 mg BID did not result in accumulation of drug.”

Dr Curnutte also noted that enrollment of CLL/SLL patients is complete, and investigators would be “very careful” if the study were to be re-opened to these patients.

For now, Portola is focused on completing enrollment in other patient groups on this phase 2 trial. The company is also hoping to conduct a phase 3 trial of cerdulatinib in PTCL that could begin as early as the end of this year.

Poster session at the 23rd Congress of the European Hematology Association

STOCKHOLM—The dual SYK/JAK inhibitor cerdulatinib has demonstrated efficacy in a phase 2 trial of patients with heavily pretreated B- and T-cell non-Hodgkin lymphomas (NHLs).

There were a few deaths due to sepsis or septic shock that were considered related to cerdulatinib, but investigators have taken steps to prevent additional deaths.

Cerdulatinib produced responses in patients with peripheral T-cell lymphoma (PTCL), cutaneous T-cell lymphoma (CTCL), chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), follicular lymphoma (FL), and other NHLs.

The 5 deaths due to sepsis or septic shock (3 concomitant with pneumonia) occurred early on in the trial, and dose reductions, monitoring, and antibiotic prophylaxis appeared to be effective in preventing additional deaths.

Results from this trial were presented in a poster (abstract PF437) at the 23rd Congress of the European Hematology Association (EHA).

The research was sponsored by Portola Pharmaceuticals, Inc.

The trial enrolled 114 patients. They had FL (grade 1-3A; n=39), PTCL (n=25), CTCL (n=5), CLL/SLL (n=28), other indolent NHLs (Waldenstrom’s macroglobulinemia and marginal zone lymphoma; n=12), or aggressive NHL (defined as diffuse large B-cell lymphoma [DLBCL], grade 3B FL, mantle cell lymphoma, and transformed NHL with relapsed disease; n=5).

The patients’ median age was 68 (range, 34-93), and 59% were male. The median number of prior treatment regimens was 3 (range, 1-13), and 37% of patients had refractory disease.

Patients received cerdulatinib at 25, 30, or 35 mg twice daily (BID). A total of 101 patients were evaluable as of May 4, 2018.

Response

The objective response rate (ORR) was 47% in the entire population. Thirteen patients achieved a complete response (CR), and 34 had a partial response (PR). Thirty-four patients remained on cerdulatinib at the data cut-off.

The ORR was 46% in the FL patients, with 3 patients achieving a CR and 13 achieving a PR. Thirteen FL patients remained on cerdulatinib.

In the CLL/SLL patients, the ORR was 61%. Two patients had a CR, and 15 had a PR. Four CLL/SLL patients remained on cerdulatinib.

In PTCL, the ORR was 35%. All 7 responders had a CR. Eleven PTCL patients remained on cerdulatinib.

Only 1 CTCL patient was evaluable, but this patient achieved a CR and remained on cerdulatinib.

The ORR was 42% for patients with other indolent NHLs, with 5 PRs and no CRs. Only 1 patient in this group remained on cerdulatinib.

For aggressive NHL, the ORR was 20%, with 1 PR and no CRs. None of the patients in this group stayed on cerdulatinib.

“Cerdulatinib continues to demonstrate promising results across a wide range of B- and T-cell malignancies, including early indications of the potential for durable responses,” said study investigator Paul Hamlin, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

“The new signals in relapsed/refractory PTCL and CTCL are particularly compelling when you consider the limited treatment options for patients that fail frontline therapy.”

Safety

Grade 3 or higher adverse events included lipase increase (18%), neutropenia (17%), pneumonia/lung infection (11%), diarrhea (8%), fatigue (6%), amylase increase (5%), sepsis/septic shock (4%), hypertension (4%), anemia (4%), thrombocytopenia (4%), and hypophosphatemia (4%).

The 5 deaths due to sepsis or septic shock (3 of which were concomitant with pneumonia) were considered related to cerdulatinib. Three of the deaths occurred in patients with CLL, 1 in a DLBCL patient, and 1 in an FL patient.

“One of the things we have seen [with CLL patients] is the background infection rate is quite a bit higher,” said John T. Curnutte, MD, PhD, interim co-president and head of research and development at Portola Pharmaceuticals.

“You see this with multiple other agents, so we were not particularly surprised to see [sepsis/septic shock in CLL].”

Dr Curnutte noted that grade 5 sepsis/septic shock tended to occur in patients who were pre-colonized and/or had high plasma levels of cerdulatinib.

So, to prevent these adverse events, the starting dose of cerdulatinib was lowered, investigators began monitoring patients’ plasma levels, and all patients began receiving antibiotic prophylaxis. (Previously, only CLL patients had received this prophylaxis.)

The investigators found that lowering the starting dose from 35 mg BID to 30 mg or even 25 mg BID reduced plasma levels.

“At the 35 mg dose, 1 out of every 4 patients showed accumulation of the drug,” Dr Curnutte said. “In general, the use of the 30 mg BID or step-down 25 mg BID did not result in accumulation of drug.”

Dr Curnutte also noted that enrollment of CLL/SLL patients is complete, and investigators would be “very careful” if the study were to be re-opened to these patients.

For now, Portola is focused on completing enrollment in other patient groups on this phase 2 trial. The company is also hoping to conduct a phase 3 trial of cerdulatinib in PTCL that could begin as early as the end of this year.

CHICAGO – Chemoimmunotherapy for chronic lymphocytic leukemia is on the way out, but there’s one scenario where it still plays a key role, according to one leukemia expert.

That scenario is not in relapsed or refractory chronic lymphocytic leukemia (CLL), where the use of fludarabine, cyclophosphamide, and rituximab (FCR) may be hard to justify today. Data supporting use of FCR in relapsed CLL show a median progression-free survival (PFS) of about 21 months, Susan M. O’Brien, MD, of the University of California, Irvine, said at the annual meeting of the American Society of Clinical Oncology. There is also data for bendamustine-rituximab retreatment showing a median event-free survival of about 15 months, she added.

By contrast, the 5-year follow-up data for the Bruton tyrosine kinase inhibitor ibrutinib in the relapsed/refractory setting shows a median PFS of 52 months, which is “extraordinary,” given that the patients had a median of four prior regimens, Dr. O’Brien said.

Similarly, recently published results from the randomized, phase 3 MURANO study of venetoclax plus rituximab in relapsed/refractory CLL showed that median PFS was not reached at a median follow-up of 23.8 months, versus a median of 17 months for the bendamustine-rituximab comparison arm (N Engl J Med. 2018;378[12]:1107-20).

“Thanks to the MURANO study, we likely will have an expanded label for venetoclax that includes the combination of venetoclax and rituximab,” Dr. O’Brien said. “I think it’s quite clear that either of these is dramatically better than what you get with retreatment with chemotherapy, so I personally don’t think there is a role for chemoimmunotherapy in the relapsed patient.”

On June 8, 2018, the Food and Drug Administration granted regular approval for venetoclax for patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy. The FDA also approved its use in combination with rituximab.*

But frontline CLL treatment is currently a little bit more complicated, Dr. O’Brien said.

Recent studies show favorable long-term outcomes with FCR frontline therapy in the immunoglobulin heavy chain variable gene (IgHV) –mutated subgroup of patients, she noted.

The longest follow-up comes from a study from investigators at the University of Texas MD Anderson Cancer Center, Houston, published in 2016. In that study, the 12.8-year PFS was 53.9% for IgHV-mutated patients, versus just 8.7% for patients with unmutated IgHV. Of the IgHV-mutated group, more than half achieved minimal residual disease (MRD) negativity after treatment (Blood. 2016 Jan 21; 127[3]: 303-9).

“I’m going to go out on a limb and I’m going to suggest that I think there is a cure fraction here,” Dr. O’Brien said. “On the other hand, if there’s not a cure fraction and they’re going to relapse after 17 years, that’s a pretty attractive endpoint, even if it’s not a cure fraction.”

Clinical practice guidelines now recognize IgHV mutation status as an important marker that should be obtained when deciding on treatment, Dr. O’Brien noted.

For unmutated patients, the RESONATE-2 trial showed that ibrutinib was superior to chlorambucil in older patients, many of whom had comorbid conditions. In the 3-year update, median PFS was approximately 15 months for chlorambucil, while for ibrutinib the median PFS was “nowhere near” being reached, Dr. O’Brien said.

Those data may not be so relevant for fit, unmutated patients, and two randomized trials comparing FCR with bendamustine and rituximab have yet to report data. However, one recent cross-trial comparison found fairly overlapping survival curves for the two chemoimmunotherapy approaches.

Dr. O’Brien said she would put older patients with comorbidities on ibrutinib if a clinical trial was not available, and for fit, unmutated patients, while more data are needed, she would also use ibrutinib. However, patient preference sometimes tips the scale in favor of FCR.

“The discussions sometimes are quite long about whether the patient should opt to take ibrutinib or FCR,” Dr. O’Brien said. “The last patient I had that discussion with elected to take FCR. When I asked him why, he said because he liked the idea of being finished in six cycles, off all therapy, and hopefully in remission.”

While Dr. O’Brien said she views chemoimmunotherapy as still relevant in IgHV-mutated patients, eventually it will go away, she concluded. Toward that end, there is considerable interest in venetoclax plus ibrutinib, a combination that, in early reports, has yielded very encouraging MRD results in first-line CLL.

“We have no long-term data, but very, very exciting MRD negativity data,” Dr. O’Brien said.

Dr. O’Brien reported relationships with Abbvie, Amgen, Celgene, Gilead Sciences, Janssen, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, and others.

*This story was updated 6/25/2018.

CHICAGO – Chemoimmunotherapy for chronic lymphocytic leukemia is on the way out, but there’s one scenario where it still plays a key role, according to one leukemia expert.

That scenario is not in relapsed or refractory chronic lymphocytic leukemia (CLL), where the use of fludarabine, cyclophosphamide, and rituximab (FCR) may be hard to justify today. Data supporting use of FCR in relapsed CLL show a median progression-free survival (PFS) of about 21 months, Susan M. O’Brien, MD, of the University of California, Irvine, said at the annual meeting of the American Society of Clinical Oncology. There is also data for bendamustine-rituximab retreatment showing a median event-free survival of about 15 months, she added.

By contrast, the 5-year follow-up data for the Bruton tyrosine kinase inhibitor ibrutinib in the relapsed/refractory setting shows a median PFS of 52 months, which is “extraordinary,” given that the patients had a median of four prior regimens, Dr. O’Brien said.

Similarly, recently published results from the randomized, phase 3 MURANO study of venetoclax plus rituximab in relapsed/refractory CLL showed that median PFS was not reached at a median follow-up of 23.8 months, versus a median of 17 months for the bendamustine-rituximab comparison arm (N Engl J Med. 2018;378[12]:1107-20).

“Thanks to the MURANO study, we likely will have an expanded label for venetoclax that includes the combination of venetoclax and rituximab,” Dr. O’Brien said. “I think it’s quite clear that either of these is dramatically better than what you get with retreatment with chemotherapy, so I personally don’t think there is a role for chemoimmunotherapy in the relapsed patient.”

On June 8, 2018, the Food and Drug Administration granted regular approval for venetoclax for patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy. The FDA also approved its use in combination with rituximab.*

But frontline CLL treatment is currently a little bit more complicated, Dr. O’Brien said.

Recent studies show favorable long-term outcomes with FCR frontline therapy in the immunoglobulin heavy chain variable gene (IgHV) –mutated subgroup of patients, she noted.

The longest follow-up comes from a study from investigators at the University of Texas MD Anderson Cancer Center, Houston, published in 2016. In that study, the 12.8-year PFS was 53.9% for IgHV-mutated patients, versus just 8.7% for patients with unmutated IgHV. Of the IgHV-mutated group, more than half achieved minimal residual disease (MRD) negativity after treatment (Blood. 2016 Jan 21; 127[3]: 303-9).

“I’m going to go out on a limb and I’m going to suggest that I think there is a cure fraction here,” Dr. O’Brien said. “On the other hand, if there’s not a cure fraction and they’re going to relapse after 17 years, that’s a pretty attractive endpoint, even if it’s not a cure fraction.”

Clinical practice guidelines now recognize IgHV mutation status as an important marker that should be obtained when deciding on treatment, Dr. O’Brien noted.

For unmutated patients, the RESONATE-2 trial showed that ibrutinib was superior to chlorambucil in older patients, many of whom had comorbid conditions. In the 3-year update, median PFS was approximately 15 months for chlorambucil, while for ibrutinib the median PFS was “nowhere near” being reached, Dr. O’Brien said.

Those data may not be so relevant for fit, unmutated patients, and two randomized trials comparing FCR with bendamustine and rituximab have yet to report data. However, one recent cross-trial comparison found fairly overlapping survival curves for the two chemoimmunotherapy approaches.

Dr. O’Brien said she would put older patients with comorbidities on ibrutinib if a clinical trial was not available, and for fit, unmutated patients, while more data are needed, she would also use ibrutinib. However, patient preference sometimes tips the scale in favor of FCR.

“The discussions sometimes are quite long about whether the patient should opt to take ibrutinib or FCR,” Dr. O’Brien said. “The last patient I had that discussion with elected to take FCR. When I asked him why, he said because he liked the idea of being finished in six cycles, off all therapy, and hopefully in remission.”

While Dr. O’Brien said she views chemoimmunotherapy as still relevant in IgHV-mutated patients, eventually it will go away, she concluded. Toward that end, there is considerable interest in venetoclax plus ibrutinib, a combination that, in early reports, has yielded very encouraging MRD results in first-line CLL.

“We have no long-term data, but very, very exciting MRD negativity data,” Dr. O’Brien said.

Dr. O’Brien reported relationships with Abbvie, Amgen, Celgene, Gilead Sciences, Janssen, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, and others.

*This story was updated 6/25/2018.

CHICAGO – Chemoimmunotherapy for chronic lymphocytic leukemia is on the way out, but there’s one scenario where it still plays a key role, according to one leukemia expert.

That scenario is not in relapsed or refractory chronic lymphocytic leukemia (CLL), where the use of fludarabine, cyclophosphamide, and rituximab (FCR) may be hard to justify today. Data supporting use of FCR in relapsed CLL show a median progression-free survival (PFS) of about 21 months, Susan M. O’Brien, MD, of the University of California, Irvine, said at the annual meeting of the American Society of Clinical Oncology. There is also data for bendamustine-rituximab retreatment showing a median event-free survival of about 15 months, she added.

By contrast, the 5-year follow-up data for the Bruton tyrosine kinase inhibitor ibrutinib in the relapsed/refractory setting shows a median PFS of 52 months, which is “extraordinary,” given that the patients had a median of four prior regimens, Dr. O’Brien said.

Similarly, recently published results from the randomized, phase 3 MURANO study of venetoclax plus rituximab in relapsed/refractory CLL showed that median PFS was not reached at a median follow-up of 23.8 months, versus a median of 17 months for the bendamustine-rituximab comparison arm (N Engl J Med. 2018;378[12]:1107-20).

“Thanks to the MURANO study, we likely will have an expanded label for venetoclax that includes the combination of venetoclax and rituximab,” Dr. O’Brien said. “I think it’s quite clear that either of these is dramatically better than what you get with retreatment with chemotherapy, so I personally don’t think there is a role for chemoimmunotherapy in the relapsed patient.”

On June 8, 2018, the Food and Drug Administration granted regular approval for venetoclax for patients with CLL or small lymphocytic lymphoma, with or without 17p deletion, who have received at least one prior therapy. The FDA also approved its use in combination with rituximab.*

But frontline CLL treatment is currently a little bit more complicated, Dr. O’Brien said.

Recent studies show favorable long-term outcomes with FCR frontline therapy in the immunoglobulin heavy chain variable gene (IgHV) –mutated subgroup of patients, she noted.

The longest follow-up comes from a study from investigators at the University of Texas MD Anderson Cancer Center, Houston, published in 2016. In that study, the 12.8-year PFS was 53.9% for IgHV-mutated patients, versus just 8.7% for patients with unmutated IgHV. Of the IgHV-mutated group, more than half achieved minimal residual disease (MRD) negativity after treatment (Blood. 2016 Jan 21; 127[3]: 303-9).

“I’m going to go out on a limb and I’m going to suggest that I think there is a cure fraction here,” Dr. O’Brien said. “On the other hand, if there’s not a cure fraction and they’re going to relapse after 17 years, that’s a pretty attractive endpoint, even if it’s not a cure fraction.”

Clinical practice guidelines now recognize IgHV mutation status as an important marker that should be obtained when deciding on treatment, Dr. O’Brien noted.

For unmutated patients, the RESONATE-2 trial showed that ibrutinib was superior to chlorambucil in older patients, many of whom had comorbid conditions. In the 3-year update, median PFS was approximately 15 months for chlorambucil, while for ibrutinib the median PFS was “nowhere near” being reached, Dr. O’Brien said.

Those data may not be so relevant for fit, unmutated patients, and two randomized trials comparing FCR with bendamustine and rituximab have yet to report data. However, one recent cross-trial comparison found fairly overlapping survival curves for the two chemoimmunotherapy approaches.

Dr. O’Brien said she would put older patients with comorbidities on ibrutinib if a clinical trial was not available, and for fit, unmutated patients, while more data are needed, she would also use ibrutinib. However, patient preference sometimes tips the scale in favor of FCR.

“The discussions sometimes are quite long about whether the patient should opt to take ibrutinib or FCR,” Dr. O’Brien said. “The last patient I had that discussion with elected to take FCR. When I asked him why, he said because he liked the idea of being finished in six cycles, off all therapy, and hopefully in remission.”

While Dr. O’Brien said she views chemoimmunotherapy as still relevant in IgHV-mutated patients, eventually it will go away, she concluded. Toward that end, there is considerable interest in venetoclax plus ibrutinib, a combination that, in early reports, has yielded very encouraging MRD results in first-line CLL.

“We have no long-term data, but very, very exciting MRD negativity data,” Dr. O’Brien said.

Dr. O’Brien reported relationships with Abbvie, Amgen, Celgene, Gilead Sciences, Janssen, Pfizer, Pharmacyclics, Sunesis Pharmaceuticals, and others.

*This story was updated 6/25/2018.

Valentin Goede, MD

STOCKHOLM—Obinutuzumab plus chlorambucil (G-Clb) is a “valid and beneficial” frontline treatment option for “unfit” patients with chronic lymphocytic leukemia (CLL), according to a speaker at the 23rd Congress of the European Hematology Association (EHA).

Final results from the CLL11 study have revealed additional benefits of G-Clb over rituximab plus chlorambucil (R-Clb) in patients with previously untreated CLL and comorbidities.

Prior results from this study showed that G-Clb produced higher response rates and prolonged progression-fee survival (PFS) compared to R-Clb.

Now, with a median follow-up of 5 years, researchers have found that G-Clb prolongs overall survival (OS) and time to next treatment (TTNT) as well.

Valentin Goede, MD, of the University Hospital Cologne in Germany, presented these results during the Presidential Symposium of the EHA Congress (abstract S151).

The study was sponsored by Hoffmann-La Roche.

CLL11 enrolled patients with previously untreated CLL and coexisting medical conditions. They were randomized to receive six 28-day cycles of Clb alone, G-Clb, or R-Clb.

In stage 1, researchers compared G-Clb (n=238) to Clb alone (n=118) and R-Clb (n=233) to Clb alone (n=118). In stage 2, they compared G-Clb (n=333) and R-Clb (n=330).

“The treatment arms were well-balanced, not just with regard to patient [characteristics] but also with disease characteristics,” Dr Goede said.

Overall, the median age was 73 (range, 39-90), the median Cumulative Illness Rating Scale score was 8, and the median creatinine clearance was 62 mL/min.

Efficacy: G-Clb vs Clb

The median observation time for G-Clb vs Clb was 62.5 months.

The median PFS was 31.1 months in the G-Clb arm and 11.1 months in the Clb arm. The 5-year PFS rates were 25% and 2%, respectively. The hazard ratio (HR) was 0.21 (P<0.0001).

The median OS was not reached in the G-Clb arm and was 66.7 months in the Clb arm. The 5-year OS rates were 66% and 53%, respectively. The HR was 0.68 (P=0.0196).

Thirty-nine percent of the G-Clb arm died, as did 49% of the Clb arm. The main causes of death were adverse events (AEs) and disease progression.

Efficacy: G-Clb vs R-Clb

The median observation time for G-Clb vs R-Clb was 59.4 months.

The median PFS was 28.9 months in the G-Clb arm and 15.7 months in the R-Clb arm. The 5-year PFS rates were 23% and 9%, respectively. The HR was 0.49 (P<0.0001).

“The median PFS was nearly doubled, from approximately 15 months in the rituximab arm to almost 30 months in the obinutuzumab arm,” Dr Goede said. “And this translated into a clinically meaningful prolongation of time to next treatment.”

The median TTNT was 56.4 months in the G-Clb arm and 34.9 months in the R-Clb arm. At 5 years, TTNT rates were 49% and 32%, respectively. The HR was 0.58 (P<0.0001).

“In the rituximab arm, the median time to next treatment was a little greater than 2.5 years, and, in the obinutuzumab arm, it was almost 5 years,” Dr Goede said. “From a clinical perspective, I would consider treatment-free intervals of that duration as highly relevant and beneficial in an elderly population.”

The median OS was not reached in the G-Clb arm and was 73.1 months in the R-Clb arm. The 5-year OS rates were 66% and 57%, respectively. The HR was 0.76 (P=0.0245).

“This difference is clinically meaningful, and it is also remarkable in the context of the long follow-up, given the fact that approximately half of the patients have received at least 1 salvage treatment in the meantime,” Dr Goede said.

In all, 37% of the G-Clb arm died, as did 45% of the R-Clb arm. Again, the main causes of death were AEs and disease progression.

Safety

Dr Goede said no new safety signals or late-onset toxicities were detected.

“Adverse events of any grade, but particularly grade 3-5 and serious adverse events, were more frequent in the obinutuzumab arm compared to the other 2 arms,” he noted. “[This] was mainly driven by more infusion reactions and some greater hematological toxicity.”

“Importantly, the rate of fatal adverse events, during treatment but also during follow-up, was not higher in the obinutuzumab arm. And the most common fatal adverse events were second malignancies.”

G-Clb vs Clb

Ninety-five percent of patients in the G-Clb arm and 83% of those in the Clb arm had at least 1 AE. The rates of grade 3-5 AEs were 74% and 51%, respectively. The rates of serious AEs were 47% and 39%, respectively. The rates of fatal AEs were 8% and 11%, respectively.

Seventeen percent of patients in the G-Clb arm and 11% of those in the Clb arm had late-onset neutropenia. The rates of prolonged neutropenia were 3% and 9%, respectively.

Fourteen percent of patients in the G-Clb arm and 7% of those in the Clb arm had second malignancies (starting 6 months after treatment initiation). The most common of these were squamous cell carcinoma (2% vs 0%) and basal cell carcinoma (2% vs <1%).

G-Clb vs R-Clb

Ninety-four percent of patients in the G-Clb arm and 90% of those in the R-Clb arm had at least 1 AE. The rates of grade 3-5 AEs were 72% and 60%, respectively. The rates of serious AEs were 45% and 39%, respectively. The rates of fatal AEs were 7% and 10%, respectively.

Fifteen percent of patients in the G-Clb arm and 12% of those in the R-Clb arm had late-onset neutropenia. The rates of prolonged neutropenia were 2% and 4%, respectively.

Eleven percent of patients in the G-Clb arm and 10% of those in the Clb arm had second malignancies. Squamous cell carcinoma occurred in 2% of patients in both arms. Basal cell carcinoma occurred in 2% of G-Clb recipients and 1% of R-Clb recipients.

Valentin Goede, MD

STOCKHOLM—Obinutuzumab plus chlorambucil (G-Clb) is a “valid and beneficial” frontline treatment option for “unfit” patients with chronic lymphocytic leukemia (CLL), according to a speaker at the 23rd Congress of the European Hematology Association (EHA).

Final results from the CLL11 study have revealed additional benefits of G-Clb over rituximab plus chlorambucil (R-Clb) in patients with previously untreated CLL and comorbidities.

Prior results from this study showed that G-Clb produced higher response rates and prolonged progression-fee survival (PFS) compared to R-Clb.

Now, with a median follow-up of 5 years, researchers have found that G-Clb prolongs overall survival (OS) and time to next treatment (TTNT) as well.

Valentin Goede, MD, of the University Hospital Cologne in Germany, presented these results during the Presidential Symposium of the EHA Congress (abstract S151).

The study was sponsored by Hoffmann-La Roche.

CLL11 enrolled patients with previously untreated CLL and coexisting medical conditions. They were randomized to receive six 28-day cycles of Clb alone, G-Clb, or R-Clb.

In stage 1, researchers compared G-Clb (n=238) to Clb alone (n=118) and R-Clb (n=233) to Clb alone (n=118). In stage 2, they compared G-Clb (n=333) and R-Clb (n=330).

“The treatment arms were well-balanced, not just with regard to patient [characteristics] but also with disease characteristics,” Dr Goede said.

Overall, the median age was 73 (range, 39-90), the median Cumulative Illness Rating Scale score was 8, and the median creatinine clearance was 62 mL/min.

Efficacy: G-Clb vs Clb

The median observation time for G-Clb vs Clb was 62.5 months.

The median PFS was 31.1 months in the G-Clb arm and 11.1 months in the Clb arm. The 5-year PFS rates were 25% and 2%, respectively. The hazard ratio (HR) was 0.21 (P<0.0001).

The median OS was not reached in the G-Clb arm and was 66.7 months in the Clb arm. The 5-year OS rates were 66% and 53%, respectively. The HR was 0.68 (P=0.0196).

Thirty-nine percent of the G-Clb arm died, as did 49% of the Clb arm. The main causes of death were adverse events (AEs) and disease progression.

Efficacy: G-Clb vs R-Clb

The median observation time for G-Clb vs R-Clb was 59.4 months.

The median PFS was 28.9 months in the G-Clb arm and 15.7 months in the R-Clb arm. The 5-year PFS rates were 23% and 9%, respectively. The HR was 0.49 (P<0.0001).

“The median PFS was nearly doubled, from approximately 15 months in the rituximab arm to almost 30 months in the obinutuzumab arm,” Dr Goede said. “And this translated into a clinically meaningful prolongation of time to next treatment.”

The median TTNT was 56.4 months in the G-Clb arm and 34.9 months in the R-Clb arm. At 5 years, TTNT rates were 49% and 32%, respectively. The HR was 0.58 (P<0.0001).

“In the rituximab arm, the median time to next treatment was a little greater than 2.5 years, and, in the obinutuzumab arm, it was almost 5 years,” Dr Goede said. “From a clinical perspective, I would consider treatment-free intervals of that duration as highly relevant and beneficial in an elderly population.”

The median OS was not reached in the G-Clb arm and was 73.1 months in the R-Clb arm. The 5-year OS rates were 66% and 57%, respectively. The HR was 0.76 (P=0.0245).

“This difference is clinically meaningful, and it is also remarkable in the context of the long follow-up, given the fact that approximately half of the patients have received at least 1 salvage treatment in the meantime,” Dr Goede said.

In all, 37% of the G-Clb arm died, as did 45% of the R-Clb arm. Again, the main causes of death were AEs and disease progression.

Safety

Dr Goede said no new safety signals or late-onset toxicities were detected.

“Adverse events of any grade, but particularly grade 3-5 and serious adverse events, were more frequent in the obinutuzumab arm compared to the other 2 arms,” he noted. “[This] was mainly driven by more infusion reactions and some greater hematological toxicity.”

“Importantly, the rate of fatal adverse events, during treatment but also during follow-up, was not higher in the obinutuzumab arm. And the most common fatal adverse events were second malignancies.”

G-Clb vs Clb

Ninety-five percent of patients in the G-Clb arm and 83% of those in the Clb arm had at least 1 AE. The rates of grade 3-5 AEs were 74% and 51%, respectively. The rates of serious AEs were 47% and 39%, respectively. The rates of fatal AEs were 8% and 11%, respectively.

Seventeen percent of patients in the G-Clb arm and 11% of those in the Clb arm had late-onset neutropenia. The rates of prolonged neutropenia were 3% and 9%, respectively.

Fourteen percent of patients in the G-Clb arm and 7% of those in the Clb arm had second malignancies (starting 6 months after treatment initiation). The most common of these were squamous cell carcinoma (2% vs 0%) and basal cell carcinoma (2% vs <1%).

G-Clb vs R-Clb

Ninety-four percent of patients in the G-Clb arm and 90% of those in the R-Clb arm had at least 1 AE. The rates of grade 3-5 AEs were 72% and 60%, respectively. The rates of serious AEs were 45% and 39%, respectively. The rates of fatal AEs were 7% and 10%, respectively.

Fifteen percent of patients in the G-Clb arm and 12% of those in the R-Clb arm had late-onset neutropenia. The rates of prolonged neutropenia were 2% and 4%, respectively.

Eleven percent of patients in the G-Clb arm and 10% of those in the Clb arm had second malignancies. Squamous cell carcinoma occurred in 2% of patients in both arms. Basal cell carcinoma occurred in 2% of G-Clb recipients and 1% of R-Clb recipients.

Valentin Goede, MD

STOCKHOLM—Obinutuzumab plus chlorambucil (G-Clb) is a “valid and beneficial” frontline treatment option for “unfit” patients with chronic lymphocytic leukemia (CLL), according to a speaker at the 23rd Congress of the European Hematology Association (EHA).

Final results from the CLL11 study have revealed additional benefits of G-Clb over rituximab plus chlorambucil (R-Clb) in patients with previously untreated CLL and comorbidities.

Prior results from this study showed that G-Clb produced higher response rates and prolonged progression-fee survival (PFS) compared to R-Clb.

Now, with a median follow-up of 5 years, researchers have found that G-Clb prolongs overall survival (OS) and time to next treatment (TTNT) as well.

Valentin Goede, MD, of the University Hospital Cologne in Germany, presented these results during the Presidential Symposium of the EHA Congress (abstract S151).

The study was sponsored by Hoffmann-La Roche.

CLL11 enrolled patients with previously untreated CLL and coexisting medical conditions. They were randomized to receive six 28-day cycles of Clb alone, G-Clb, or R-Clb.

In stage 1, researchers compared G-Clb (n=238) to Clb alone (n=118) and R-Clb (n=233) to Clb alone (n=118). In stage 2, they compared G-Clb (n=333) and R-Clb (n=330).

“The treatment arms were well-balanced, not just with regard to patient [characteristics] but also with disease characteristics,” Dr Goede said.

Overall, the median age was 73 (range, 39-90), the median Cumulative Illness Rating Scale score was 8, and the median creatinine clearance was 62 mL/min.

Efficacy: G-Clb vs Clb

The median observation time for G-Clb vs Clb was 62.5 months.

The median PFS was 31.1 months in the G-Clb arm and 11.1 months in the Clb arm. The 5-year PFS rates were 25% and 2%, respectively. The hazard ratio (HR) was 0.21 (P<0.0001).

The median OS was not reached in the G-Clb arm and was 66.7 months in the Clb arm. The 5-year OS rates were 66% and 53%, respectively. The HR was 0.68 (P=0.0196).

Thirty-nine percent of the G-Clb arm died, as did 49% of the Clb arm. The main causes of death were adverse events (AEs) and disease progression.

Efficacy: G-Clb vs R-Clb

The median observation time for G-Clb vs R-Clb was 59.4 months.

The median PFS was 28.9 months in the G-Clb arm and 15.7 months in the R-Clb arm. The 5-year PFS rates were 23% and 9%, respectively. The HR was 0.49 (P<0.0001).

“The median PFS was nearly doubled, from approximately 15 months in the rituximab arm to almost 30 months in the obinutuzumab arm,” Dr Goede said. “And this translated into a clinically meaningful prolongation of time to next treatment.”

The median TTNT was 56.4 months in the G-Clb arm and 34.9 months in the R-Clb arm. At 5 years, TTNT rates were 49% and 32%, respectively. The HR was 0.58 (P<0.0001).

“In the rituximab arm, the median time to next treatment was a little greater than 2.5 years, and, in the obinutuzumab arm, it was almost 5 years,” Dr Goede said. “From a clinical perspective, I would consider treatment-free intervals of that duration as highly relevant and beneficial in an elderly population.”

The median OS was not reached in the G-Clb arm and was 73.1 months in the R-Clb arm. The 5-year OS rates were 66% and 57%, respectively. The HR was 0.76 (P=0.0245).

“This difference is clinically meaningful, and it is also remarkable in the context of the long follow-up, given the fact that approximately half of the patients have received at least 1 salvage treatment in the meantime,” Dr Goede said.

In all, 37% of the G-Clb arm died, as did 45% of the R-Clb arm. Again, the main causes of death were AEs and disease progression.

Safety

Dr Goede said no new safety signals or late-onset toxicities were detected.

“Adverse events of any grade, but particularly grade 3-5 and serious adverse events, were more frequent in the obinutuzumab arm compared to the other 2 arms,” he noted. “[This] was mainly driven by more infusion reactions and some greater hematological toxicity.”

“Importantly, the rate of fatal adverse events, during treatment but also during follow-up, was not higher in the obinutuzumab arm. And the most common fatal adverse events were second malignancies.”

G-Clb vs Clb

Ninety-five percent of patients in the G-Clb arm and 83% of those in the Clb arm had at least 1 AE. The rates of grade 3-5 AEs were 74% and 51%, respectively. The rates of serious AEs were 47% and 39%, respectively. The rates of fatal AEs were 8% and 11%, respectively.

Seventeen percent of patients in the G-Clb arm and 11% of those in the Clb arm had late-onset neutropenia. The rates of prolonged neutropenia were 3% and 9%, respectively.

Fourteen percent of patients in the G-Clb arm and 7% of those in the Clb arm had second malignancies (starting 6 months after treatment initiation). The most common of these were squamous cell carcinoma (2% vs 0%) and basal cell carcinoma (2% vs <1%).

G-Clb vs R-Clb

Ninety-four percent of patients in the G-Clb arm and 90% of those in the R-Clb arm had at least 1 AE. The rates of grade 3-5 AEs were 72% and 60%, respectively. The rates of serious AEs were 45% and 39%, respectively. The rates of fatal AEs were 7% and 10%, respectively.

Fifteen percent of patients in the G-Clb arm and 12% of those in the R-Clb arm had late-onset neutropenia. The rates of prolonged neutropenia were 2% and 4%, respectively.

Eleven percent of patients in the G-Clb arm and 10% of those in the Clb arm had second malignancies. Squamous cell carcinoma occurred in 2% of patients in both arms. Basal cell carcinoma occurred in 2% of G-Clb recipients and 1% of R-Clb recipients.