B Cell Lymphoma

New research suggests a gene expression signature can distinguish high-grade diffuse large B-cell lymphomas (DLBCLs) from other germinal center B-cell–like (GCB) DLBCLs.

Gio_tto/Thinkstock

Researchers identified GCB DLBCL patients with this 104-gene signature who had a “distinct mutational landscape” and inferior treatment outcomes. David W. Scott, MBChB, PhD, of the British Columbia Cancer Research Centre in Vancouver, and his colleagues described these patients in the Journal of Clinical Oncology.

The findings were published alongside a related editorial and a similar study from another group.

Dr. Scott and his colleagues began their study by analyzing data from 157 patients with de novo GCB DLBCL. Twenty-five of these patients had double- or triple-hit high-grade B-cell lymphoma with BCL2 translocations (HGBL-DH/TH-BCL2).

The researchers identified 104 genes that were the “most significantly differentially expressed between HGBL-DH/TH-BCL2 and other GCB DLBCLs” to create their double-hit gene signature (DHITsig).

The signature divided the patients into two groups — 42 patients (27%) whose tumors were positive for the DHITsig and 115 (73%) whose tumors were negative. Notably, 22 of the 25 HGBL-DH/TH-BCL2 tumors were DHITsig-positive and 3 were negative.

The DHITsig was not associated with clinical variables such as tumor volume, but it was associated with prognosis. Treatment outcomes were inferior in patients who were DHITsig-positive.

The 5-year time to progression rate was 81% in patients who were DHITsig-negative and 57% in those who were positive (P less than .001). The 5-year overall survival rate was 81% and 60%, respectively (P = .001).

The researchers observed similar results in a validation cohort of 262 patients with GCB-DLBCL who received rituximab-based therapy. The 5-year overall survival rate was 76% in patients who were DHITsig-negative and 49% in those who were positive (P less than .001).

Dr. Scott and his colleagues also evaluated the DHITsig in a second validation cohort of 162 patients with GCB DLBCL.

In analyzing data from all three cohorts, the researchers found that mutations in MYC, BCL2, CREBBP, EZH2^Y646, DDX3X, TP53, and KMT2D were more frequent in DHITsig-positive patients and mutations in TNFAIP3, KLHL6, NFKBIE, TET2, CD58, and STAT3 were more common in DHITsig-negative patients.

Additional analyses suggested the cell of origin for DHITsig-positive tumors comes from the intermediate zone or dark zone of the germinal center.

Finally, the researchers found they could use a “clinically relevant assay” to detect the DHITsig. They added a 30-gene module to the Lymph3Cx assay to create a NanoString-based assay called DLBCL90.

The team tested DLBCL90 in 171 GCB DLBCL patients. In this group, 26% of patients were DHITsig-positive, 64% were negative, and 10% were indeterminate. The prognostic significance of the signature was maintained with the assay results, according to the researchers.

Dr. Scott and his colleagues also wanted to validate the association between the DHITsig and HGBL-DH/TH-BCL2, so they tested the DLBCL90 assay in two additional groups of patients.

First, the assay was used in 88 patients who had transformed follicular lymphoma with DLBCL morphology. Eleven of the 25 DHITsig-positive tumors and 4 of the 13 DHITsig-indeterminate tumors were HGBL-DH/TH-BCL2. However, none of the 50 DHITsig-negative tumors were HGBL-DH/TH-BCL2.

The researchers then used the DLBCL90 assay on 26 HGBL tumors. Twenty-three of these were DHITsig-positive and 3 were indeterminate.

This research was supported by the Canadian Cancer Society Research Institute and other organizations. The researchers reported relationships with Seattle Genetics, Roche, Janssen, Celgene, and various other companies.

[email protected]

SOURCE: Scott DW et al. J Clin Oncol. 2019 Jan 20;37(3):190-201.
 

New research suggests a gene expression signature can distinguish high-grade diffuse large B-cell lymphomas (DLBCLs) from other germinal center B-cell–like (GCB) DLBCLs.

Gio_tto/Thinkstock

Researchers identified GCB DLBCL patients with this 104-gene signature who had a “distinct mutational landscape” and inferior treatment outcomes. David W. Scott, MBChB, PhD, of the British Columbia Cancer Research Centre in Vancouver, and his colleagues described these patients in the Journal of Clinical Oncology.

The findings were published alongside a related editorial and a similar study from another group.

Dr. Scott and his colleagues began their study by analyzing data from 157 patients with de novo GCB DLBCL. Twenty-five of these patients had double- or triple-hit high-grade B-cell lymphoma with BCL2 translocations (HGBL-DH/TH-BCL2).

The researchers identified 104 genes that were the “most significantly differentially expressed between HGBL-DH/TH-BCL2 and other GCB DLBCLs” to create their double-hit gene signature (DHITsig).

The signature divided the patients into two groups — 42 patients (27%) whose tumors were positive for the DHITsig and 115 (73%) whose tumors were negative. Notably, 22 of the 25 HGBL-DH/TH-BCL2 tumors were DHITsig-positive and 3 were negative.

The DHITsig was not associated with clinical variables such as tumor volume, but it was associated with prognosis. Treatment outcomes were inferior in patients who were DHITsig-positive.

The 5-year time to progression rate was 81% in patients who were DHITsig-negative and 57% in those who were positive (P less than .001). The 5-year overall survival rate was 81% and 60%, respectively (P = .001).

The researchers observed similar results in a validation cohort of 262 patients with GCB-DLBCL who received rituximab-based therapy. The 5-year overall survival rate was 76% in patients who were DHITsig-negative and 49% in those who were positive (P less than .001).

Dr. Scott and his colleagues also evaluated the DHITsig in a second validation cohort of 162 patients with GCB DLBCL.

In analyzing data from all three cohorts, the researchers found that mutations in MYC, BCL2, CREBBP, EZH2^Y646, DDX3X, TP53, and KMT2D were more frequent in DHITsig-positive patients and mutations in TNFAIP3, KLHL6, NFKBIE, TET2, CD58, and STAT3 were more common in DHITsig-negative patients.

Additional analyses suggested the cell of origin for DHITsig-positive tumors comes from the intermediate zone or dark zone of the germinal center.

Finally, the researchers found they could use a “clinically relevant assay” to detect the DHITsig. They added a 30-gene module to the Lymph3Cx assay to create a NanoString-based assay called DLBCL90.

The team tested DLBCL90 in 171 GCB DLBCL patients. In this group, 26% of patients were DHITsig-positive, 64% were negative, and 10% were indeterminate. The prognostic significance of the signature was maintained with the assay results, according to the researchers.

Dr. Scott and his colleagues also wanted to validate the association between the DHITsig and HGBL-DH/TH-BCL2, so they tested the DLBCL90 assay in two additional groups of patients.

First, the assay was used in 88 patients who had transformed follicular lymphoma with DLBCL morphology. Eleven of the 25 DHITsig-positive tumors and 4 of the 13 DHITsig-indeterminate tumors were HGBL-DH/TH-BCL2. However, none of the 50 DHITsig-negative tumors were HGBL-DH/TH-BCL2.

The researchers then used the DLBCL90 assay on 26 HGBL tumors. Twenty-three of these were DHITsig-positive and 3 were indeterminate.

This research was supported by the Canadian Cancer Society Research Institute and other organizations. The researchers reported relationships with Seattle Genetics, Roche, Janssen, Celgene, and various other companies.

[email protected]

SOURCE: Scott DW et al. J Clin Oncol. 2019 Jan 20;37(3):190-201.
 

New research suggests a gene expression signature can distinguish high-grade diffuse large B-cell lymphomas (DLBCLs) from other germinal center B-cell–like (GCB) DLBCLs.

Gio_tto/Thinkstock

Researchers identified GCB DLBCL patients with this 104-gene signature who had a “distinct mutational landscape” and inferior treatment outcomes. David W. Scott, MBChB, PhD, of the British Columbia Cancer Research Centre in Vancouver, and his colleagues described these patients in the Journal of Clinical Oncology.

The findings were published alongside a related editorial and a similar study from another group.

Dr. Scott and his colleagues began their study by analyzing data from 157 patients with de novo GCB DLBCL. Twenty-five of these patients had double- or triple-hit high-grade B-cell lymphoma with BCL2 translocations (HGBL-DH/TH-BCL2).

The researchers identified 104 genes that were the “most significantly differentially expressed between HGBL-DH/TH-BCL2 and other GCB DLBCLs” to create their double-hit gene signature (DHITsig).

The signature divided the patients into two groups — 42 patients (27%) whose tumors were positive for the DHITsig and 115 (73%) whose tumors were negative. Notably, 22 of the 25 HGBL-DH/TH-BCL2 tumors were DHITsig-positive and 3 were negative.

The DHITsig was not associated with clinical variables such as tumor volume, but it was associated with prognosis. Treatment outcomes were inferior in patients who were DHITsig-positive.

The 5-year time to progression rate was 81% in patients who were DHITsig-negative and 57% in those who were positive (P less than .001). The 5-year overall survival rate was 81% and 60%, respectively (P = .001).

The researchers observed similar results in a validation cohort of 262 patients with GCB-DLBCL who received rituximab-based therapy. The 5-year overall survival rate was 76% in patients who were DHITsig-negative and 49% in those who were positive (P less than .001).

Dr. Scott and his colleagues also evaluated the DHITsig in a second validation cohort of 162 patients with GCB DLBCL.

In analyzing data from all three cohorts, the researchers found that mutations in MYC, BCL2, CREBBP, EZH2^Y646, DDX3X, TP53, and KMT2D were more frequent in DHITsig-positive patients and mutations in TNFAIP3, KLHL6, NFKBIE, TET2, CD58, and STAT3 were more common in DHITsig-negative patients.

Additional analyses suggested the cell of origin for DHITsig-positive tumors comes from the intermediate zone or dark zone of the germinal center.

Finally, the researchers found they could use a “clinically relevant assay” to detect the DHITsig. They added a 30-gene module to the Lymph3Cx assay to create a NanoString-based assay called DLBCL90.

The team tested DLBCL90 in 171 GCB DLBCL patients. In this group, 26% of patients were DHITsig-positive, 64% were negative, and 10% were indeterminate. The prognostic significance of the signature was maintained with the assay results, according to the researchers.

Dr. Scott and his colleagues also wanted to validate the association between the DHITsig and HGBL-DH/TH-BCL2, so they tested the DLBCL90 assay in two additional groups of patients.

First, the assay was used in 88 patients who had transformed follicular lymphoma with DLBCL morphology. Eleven of the 25 DHITsig-positive tumors and 4 of the 13 DHITsig-indeterminate tumors were HGBL-DH/TH-BCL2. However, none of the 50 DHITsig-negative tumors were HGBL-DH/TH-BCL2.

The researchers then used the DLBCL90 assay on 26 HGBL tumors. Twenty-three of these were DHITsig-positive and 3 were indeterminate.

This research was supported by the Canadian Cancer Society Research Institute and other organizations. The researchers reported relationships with Seattle Genetics, Roche, Janssen, Celgene, and various other companies.

[email protected]

SOURCE: Scott DW et al. J Clin Oncol. 2019 Jan 20;37(3):190-201.
 

The Food and Drug Administration has granted priority review to a supplemental new drug application (sNDA) for lenalidomide (Revlimid).

Celgene is seeking approval for lenalidomide in combination with rituximab to treat patients with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL).

The FDA plans to make a decision on the sNDA by June 27, 2019.

The FDA aims 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 are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The sNDA for lenalidomide is supported by the phase 3 AUGMENT study (NCT01938001) in which researchers compared rituximab plus lenalidomide to rituximab plus placebo in patients with relapsed/refractory FL or MZL.

Results from AUGMENT were presented at the 2018 annual meeting of the American Society of Hematology (Blood 2018 Nov 29;132:445).

According to the ASH abstract, the trial included 358 patients who were randomized to receive rituximab plus lenalidomide (n = 178) or rituximab plus placebo (n = 180).

At a median follow-up of 28.3 months, the overall response rate was 78% in the lenalidomide arm and 53% in the placebo arm (P less than .0001). The complete response rate was 34% and 18%, respectively (P = .001).

The median progression-free survival was 39.4 months in the lenalidomide arm and 14.1 months in the placebo arm. Overall survival data were not mature, but there were 16 deaths reported in the lenalidomide arm and 26 deaths in the placebo arm.

Treatment-emergent adverse events that were more common in the lenalidomide arm than the placebo arm included infections, cutaneous reactions, constipation, thrombocytopenia, and tumor flare reaction.

[email protected]

The Food and Drug Administration has granted priority review to a supplemental new drug application (sNDA) for lenalidomide (Revlimid).

Celgene is seeking approval for lenalidomide in combination with rituximab to treat patients with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL).

The FDA plans to make a decision on the sNDA by June 27, 2019.

The FDA aims 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 are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The sNDA for lenalidomide is supported by the phase 3 AUGMENT study (NCT01938001) in which researchers compared rituximab plus lenalidomide to rituximab plus placebo in patients with relapsed/refractory FL or MZL.

Results from AUGMENT were presented at the 2018 annual meeting of the American Society of Hematology (Blood 2018 Nov 29;132:445).

According to the ASH abstract, the trial included 358 patients who were randomized to receive rituximab plus lenalidomide (n = 178) or rituximab plus placebo (n = 180).

At a median follow-up of 28.3 months, the overall response rate was 78% in the lenalidomide arm and 53% in the placebo arm (P less than .0001). The complete response rate was 34% and 18%, respectively (P = .001).

The median progression-free survival was 39.4 months in the lenalidomide arm and 14.1 months in the placebo arm. Overall survival data were not mature, but there were 16 deaths reported in the lenalidomide arm and 26 deaths in the placebo arm.

Treatment-emergent adverse events that were more common in the lenalidomide arm than the placebo arm included infections, cutaneous reactions, constipation, thrombocytopenia, and tumor flare reaction.

[email protected]

The Food and Drug Administration has granted priority review to a supplemental new drug application (sNDA) for lenalidomide (Revlimid).

Celgene is seeking approval for lenalidomide in combination with rituximab to treat patients with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL).

The FDA plans to make a decision on the sNDA by June 27, 2019.

The FDA aims 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 are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions.

The sNDA for lenalidomide is supported by the phase 3 AUGMENT study (NCT01938001) in which researchers compared rituximab plus lenalidomide to rituximab plus placebo in patients with relapsed/refractory FL or MZL.

Results from AUGMENT were presented at the 2018 annual meeting of the American Society of Hematology (Blood 2018 Nov 29;132:445).

According to the ASH abstract, the trial included 358 patients who were randomized to receive rituximab plus lenalidomide (n = 178) or rituximab plus placebo (n = 180).

At a median follow-up of 28.3 months, the overall response rate was 78% in the lenalidomide arm and 53% in the placebo arm (P less than .0001). The complete response rate was 34% and 18%, respectively (P = .001).

The median progression-free survival was 39.4 months in the lenalidomide arm and 14.1 months in the placebo arm. Overall survival data were not mature, but there were 16 deaths reported in the lenalidomide arm and 26 deaths in the placebo arm.

Treatment-emergent adverse events that were more common in the lenalidomide arm than the placebo arm included infections, cutaneous reactions, constipation, thrombocytopenia, and tumor flare reaction.

[email protected]

The high cost of chimeric antigen receptor (CAR) T-cell therapy largely limits its use to the sickest patients and prohibits experimentation in “less-diseased” populations, outcomes data suggest.

For that reason, and because bone marrow units are profit centers and CAR T-cell therapy reimbursement remains problematic, CAR T in the United States is “effectively being used as a bridge to transplant” – at a cost of more than $1 million per dose, economist Duane Schulthess told attendees at a recent, first-of-its-kind joint European CAR T-cell meeting in Paris, which was cosponsored by the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT).

“This is the way clinical practice is evolving right now; the price is not allowing enough experimentation for CAR T to flow up and be used in the less-diseased population,” said Mr. Schulthess, managing director of Vital Transformation, a consulting company based in Wezembeek-Oppem, Belgium.

In Europe, there is a slightly different problem in that health technology assessment bodies (HTAs) “have to figure out what they want to do” given the 2018 approvals of the first CAR T therapies there, he said, explaining that the data he presented was from a study commissioned by the Dutch government to help determine “what [CAR T] looks like from an effectiveness standpoint while they’re trying to figure out how much it’s worth and what they should pay.”

“Increasingly these are the big issues,” Mr. Schulthess said.

In August, the European Commission approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) on the recommendation of the European Medicines Agency. Kymriah was approved for pediatric and young adult patients up to age 25 years with refractory B-cell acute lymphoblastic leukemia in relapse after transplant or in second or later relapse, as well as for adults patients with relapsed/refractory diffuse large B-cell lymphoma after failing at least two lines of systemic therapy, and Yescarta was approved for the latter and for the treatment of primary refractory mediastinal large B-cell lymphoma after at least two lines of systemic therapy.

The approvals have researchers and clinicians there clamoring for information about the therapy, which is revolutionizing the field of hematologic malignancies, according to Christian Chabannon, MD, PhD, chair of the EBMT Cellular Therapy & Immunobiology Working Party and vice-chair of the EBMT Scientific Council.

“An increasing number of European institutions are starting to administer this new category of medicinal products and increasingly contribute to ongoing clinical protocols and preclinical studies,” Dr. Chabannon said in an interview, explaining the urgency in planning the 1st European CAR T Cell Meeting just 6 months after the CAR T approvals in Europe.

EHA and EBMT brought together patient advocates, young investigators, and experts from across the globe to present the latest relevant information and data on topics ranging from current trials and experience, CAR T implementation and management, the preclinical and clinical pipelines, various CAR T applications, industry perspectives, and relevant economic issues, he said.

The latter is where Mr. Schulthess came in.

His research involved patient-level treatment pathway data from a database of more than 3 million patients treated with either allogeneic hematopoietic stem cell transplant (allo-HCT) or CAR T therapy across 5 years of experience. The data showed up to 85% response rates for each in the first-line setting. He and his colleagues then looked at therapy choices for those who failed to respond to second-line therapies and at how decisions were made regarding transplant and CAR T therapy – and specifically whether CAR T can be a substitute for transplant.

Ultimately, they looked at 29 allo-HCT recipients and 14 CAR T therapy recipients for a head-to-head comparison of the two treatments and performed an in-depth cost-efficacy analysis using a novel “visual pathology” methodology to account for limitations in the data.

The 3-year relapse-free survival probability was nearly 68% in the transplant recipients and 46% with CAR T.

“Now why is that? [Because] ... these populations are not the same; the CAR T population has a much higher disease burden,” Mr. Schulthess said. “So what we’re seeing [among] actual clinical doctors doing this for real – they are defaulting to bone marrow transplants, except in those cases where they do not have enough time or the patient does not respond. Then and only then are they giving CAR T.”

And that comes back to the fact that bone marrow units make money, he said.

CAR T is costly, and reimbursement can be problematic; these are disincentives for doctors to use CAR T therapy, at least in the United States, and while this is currently “being worked out,” the choice more often is “giving bone marrow transplant first and seeing what happens,” Mr. Schulthess said.

In Europe, that creates “a tough choice” for the HTAs, he said, noting that, in the absence of evidence of CAR T being curative in the subpopulation of patients with high disease burden who fail transplant and given the high cost, there is a push to determine at what point it begins to make sense economically.

“We think that you gain efficiency at ... roughly $277,000 [per dose] because [at that cost] you can do more CAR Ts than you can do bone marrow transplants. [CAR T] is less invasive, it’s lighter touch, it’s more efficient,” he said. “So if we were to see an efficiency cost of between $222,000 and $277,000, we think that works.”

Another recent study came to similar conclusions based on quality assessments, he said (J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642).

“We think that’s where this is going to end up, so we think that, if someone starts producing this for a couple hundred thousand bucks, then – certainly in Europe – it will make sense for this to start drifting up and being used as a substitute [to transplant],” he added.

Mr. Schulthess was one of scores of experts and investigators who presented at the EHA/EBMT joint meeting, which included numerous U.S. pioneers in the field and young European investigators, among others, Dr. Chabannon said.

Attesting to the enthusiasm in Europe regarding CAR T, Dr. Chabannon said that there were “more requests for registration than the venue could safely accommodate, a long waiting list, and a high number of individuals on the waiting list who registered for the live streaming” of the event.

“The field of CAR T cells is growing at a fast pace since the first clinical successes reported in the early 2010s, and one can wonder whether the expectations are not in excess of what reality will deliver,” he said. “Nevertheless, CAR T cells represent an essential innovation, not an incremental progress in biomedical sciences. They combine new mechanisms of action, clinical activity in advanced malignancies (and possibly beyond the field of cancer), transfer of manufacturing of human cell-based therapeutics to the industry, and potentially the first commercial success for a gene therapy.”

Surveys conducted by various professional associations, including EBMT, have clearly identified the potential for clinical successes that CAR T cells represent and the tremendous challenges raised by these innovations, he said, noting that “these include fulfilling specific educational needs.”

Therefore, EBMT and EHA have already announced that a second edition of the meeting is planned for Jan. 30 – Feb. 1, 2020, he noted.

Mr. Schulthess reported that his research was funded by the Dutch government.

[email protected]

The high cost of chimeric antigen receptor (CAR) T-cell therapy largely limits its use to the sickest patients and prohibits experimentation in “less-diseased” populations, outcomes data suggest.

For that reason, and because bone marrow units are profit centers and CAR T-cell therapy reimbursement remains problematic, CAR T in the United States is “effectively being used as a bridge to transplant” – at a cost of more than $1 million per dose, economist Duane Schulthess told attendees at a recent, first-of-its-kind joint European CAR T-cell meeting in Paris, which was cosponsored by the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT).

“This is the way clinical practice is evolving right now; the price is not allowing enough experimentation for CAR T to flow up and be used in the less-diseased population,” said Mr. Schulthess, managing director of Vital Transformation, a consulting company based in Wezembeek-Oppem, Belgium.

In Europe, there is a slightly different problem in that health technology assessment bodies (HTAs) “have to figure out what they want to do” given the 2018 approvals of the first CAR T therapies there, he said, explaining that the data he presented was from a study commissioned by the Dutch government to help determine “what [CAR T] looks like from an effectiveness standpoint while they’re trying to figure out how much it’s worth and what they should pay.”

“Increasingly these are the big issues,” Mr. Schulthess said.

In August, the European Commission approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) on the recommendation of the European Medicines Agency. Kymriah was approved for pediatric and young adult patients up to age 25 years with refractory B-cell acute lymphoblastic leukemia in relapse after transplant or in second or later relapse, as well as for adults patients with relapsed/refractory diffuse large B-cell lymphoma after failing at least two lines of systemic therapy, and Yescarta was approved for the latter and for the treatment of primary refractory mediastinal large B-cell lymphoma after at least two lines of systemic therapy.

The approvals have researchers and clinicians there clamoring for information about the therapy, which is revolutionizing the field of hematologic malignancies, according to Christian Chabannon, MD, PhD, chair of the EBMT Cellular Therapy & Immunobiology Working Party and vice-chair of the EBMT Scientific Council.

“An increasing number of European institutions are starting to administer this new category of medicinal products and increasingly contribute to ongoing clinical protocols and preclinical studies,” Dr. Chabannon said in an interview, explaining the urgency in planning the 1st European CAR T Cell Meeting just 6 months after the CAR T approvals in Europe.

EHA and EBMT brought together patient advocates, young investigators, and experts from across the globe to present the latest relevant information and data on topics ranging from current trials and experience, CAR T implementation and management, the preclinical and clinical pipelines, various CAR T applications, industry perspectives, and relevant economic issues, he said.

The latter is where Mr. Schulthess came in.

His research involved patient-level treatment pathway data from a database of more than 3 million patients treated with either allogeneic hematopoietic stem cell transplant (allo-HCT) or CAR T therapy across 5 years of experience. The data showed up to 85% response rates for each in the first-line setting. He and his colleagues then looked at therapy choices for those who failed to respond to second-line therapies and at how decisions were made regarding transplant and CAR T therapy – and specifically whether CAR T can be a substitute for transplant.

Ultimately, they looked at 29 allo-HCT recipients and 14 CAR T therapy recipients for a head-to-head comparison of the two treatments and performed an in-depth cost-efficacy analysis using a novel “visual pathology” methodology to account for limitations in the data.

The 3-year relapse-free survival probability was nearly 68% in the transplant recipients and 46% with CAR T.

“Now why is that? [Because] ... these populations are not the same; the CAR T population has a much higher disease burden,” Mr. Schulthess said. “So what we’re seeing [among] actual clinical doctors doing this for real – they are defaulting to bone marrow transplants, except in those cases where they do not have enough time or the patient does not respond. Then and only then are they giving CAR T.”

And that comes back to the fact that bone marrow units make money, he said.

CAR T is costly, and reimbursement can be problematic; these are disincentives for doctors to use CAR T therapy, at least in the United States, and while this is currently “being worked out,” the choice more often is “giving bone marrow transplant first and seeing what happens,” Mr. Schulthess said.

In Europe, that creates “a tough choice” for the HTAs, he said, noting that, in the absence of evidence of CAR T being curative in the subpopulation of patients with high disease burden who fail transplant and given the high cost, there is a push to determine at what point it begins to make sense economically.

“We think that you gain efficiency at ... roughly $277,000 [per dose] because [at that cost] you can do more CAR Ts than you can do bone marrow transplants. [CAR T] is less invasive, it’s lighter touch, it’s more efficient,” he said. “So if we were to see an efficiency cost of between $222,000 and $277,000, we think that works.”

Another recent study came to similar conclusions based on quality assessments, he said (J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642).

“We think that’s where this is going to end up, so we think that, if someone starts producing this for a couple hundred thousand bucks, then – certainly in Europe – it will make sense for this to start drifting up and being used as a substitute [to transplant],” he added.

Mr. Schulthess was one of scores of experts and investigators who presented at the EHA/EBMT joint meeting, which included numerous U.S. pioneers in the field and young European investigators, among others, Dr. Chabannon said.

Attesting to the enthusiasm in Europe regarding CAR T, Dr. Chabannon said that there were “more requests for registration than the venue could safely accommodate, a long waiting list, and a high number of individuals on the waiting list who registered for the live streaming” of the event.

“The field of CAR T cells is growing at a fast pace since the first clinical successes reported in the early 2010s, and one can wonder whether the expectations are not in excess of what reality will deliver,” he said. “Nevertheless, CAR T cells represent an essential innovation, not an incremental progress in biomedical sciences. They combine new mechanisms of action, clinical activity in advanced malignancies (and possibly beyond the field of cancer), transfer of manufacturing of human cell-based therapeutics to the industry, and potentially the first commercial success for a gene therapy.”

Surveys conducted by various professional associations, including EBMT, have clearly identified the potential for clinical successes that CAR T cells represent and the tremendous challenges raised by these innovations, he said, noting that “these include fulfilling specific educational needs.”

Therefore, EBMT and EHA have already announced that a second edition of the meeting is planned for Jan. 30 – Feb. 1, 2020, he noted.

Mr. Schulthess reported that his research was funded by the Dutch government.

[email protected]

The high cost of chimeric antigen receptor (CAR) T-cell therapy largely limits its use to the sickest patients and prohibits experimentation in “less-diseased” populations, outcomes data suggest.

For that reason, and because bone marrow units are profit centers and CAR T-cell therapy reimbursement remains problematic, CAR T in the United States is “effectively being used as a bridge to transplant” – at a cost of more than $1 million per dose, economist Duane Schulthess told attendees at a recent, first-of-its-kind joint European CAR T-cell meeting in Paris, which was cosponsored by the European Hematology Association (EHA) and the European Society for Blood and Marrow Transplantation (EBMT).

“This is the way clinical practice is evolving right now; the price is not allowing enough experimentation for CAR T to flow up and be used in the less-diseased population,” said Mr. Schulthess, managing director of Vital Transformation, a consulting company based in Wezembeek-Oppem, Belgium.

In Europe, there is a slightly different problem in that health technology assessment bodies (HTAs) “have to figure out what they want to do” given the 2018 approvals of the first CAR T therapies there, he said, explaining that the data he presented was from a study commissioned by the Dutch government to help determine “what [CAR T] looks like from an effectiveness standpoint while they’re trying to figure out how much it’s worth and what they should pay.”

“Increasingly these are the big issues,” Mr. Schulthess said.

In August, the European Commission approved tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) on the recommendation of the European Medicines Agency. Kymriah was approved for pediatric and young adult patients up to age 25 years with refractory B-cell acute lymphoblastic leukemia in relapse after transplant or in second or later relapse, as well as for adults patients with relapsed/refractory diffuse large B-cell lymphoma after failing at least two lines of systemic therapy, and Yescarta was approved for the latter and for the treatment of primary refractory mediastinal large B-cell lymphoma after at least two lines of systemic therapy.

The approvals have researchers and clinicians there clamoring for information about the therapy, which is revolutionizing the field of hematologic malignancies, according to Christian Chabannon, MD, PhD, chair of the EBMT Cellular Therapy & Immunobiology Working Party and vice-chair of the EBMT Scientific Council.

“An increasing number of European institutions are starting to administer this new category of medicinal products and increasingly contribute to ongoing clinical protocols and preclinical studies,” Dr. Chabannon said in an interview, explaining the urgency in planning the 1st European CAR T Cell Meeting just 6 months after the CAR T approvals in Europe.

EHA and EBMT brought together patient advocates, young investigators, and experts from across the globe to present the latest relevant information and data on topics ranging from current trials and experience, CAR T implementation and management, the preclinical and clinical pipelines, various CAR T applications, industry perspectives, and relevant economic issues, he said.

The latter is where Mr. Schulthess came in.

His research involved patient-level treatment pathway data from a database of more than 3 million patients treated with either allogeneic hematopoietic stem cell transplant (allo-HCT) or CAR T therapy across 5 years of experience. The data showed up to 85% response rates for each in the first-line setting. He and his colleagues then looked at therapy choices for those who failed to respond to second-line therapies and at how decisions were made regarding transplant and CAR T therapy – and specifically whether CAR T can be a substitute for transplant.

Ultimately, they looked at 29 allo-HCT recipients and 14 CAR T therapy recipients for a head-to-head comparison of the two treatments and performed an in-depth cost-efficacy analysis using a novel “visual pathology” methodology to account for limitations in the data.

The 3-year relapse-free survival probability was nearly 68% in the transplant recipients and 46% with CAR T.

“Now why is that? [Because] ... these populations are not the same; the CAR T population has a much higher disease burden,” Mr. Schulthess said. “So what we’re seeing [among] actual clinical doctors doing this for real – they are defaulting to bone marrow transplants, except in those cases where they do not have enough time or the patient does not respond. Then and only then are they giving CAR T.”

And that comes back to the fact that bone marrow units make money, he said.

CAR T is costly, and reimbursement can be problematic; these are disincentives for doctors to use CAR T therapy, at least in the United States, and while this is currently “being worked out,” the choice more often is “giving bone marrow transplant first and seeing what happens,” Mr. Schulthess said.

In Europe, that creates “a tough choice” for the HTAs, he said, noting that, in the absence of evidence of CAR T being curative in the subpopulation of patients with high disease burden who fail transplant and given the high cost, there is a push to determine at what point it begins to make sense economically.

“We think that you gain efficiency at ... roughly $277,000 [per dose] because [at that cost] you can do more CAR Ts than you can do bone marrow transplants. [CAR T] is less invasive, it’s lighter touch, it’s more efficient,” he said. “So if we were to see an efficiency cost of between $222,000 and $277,000, we think that works.”

Another recent study came to similar conclusions based on quality assessments, he said (J Clin Oncol. 2018 Sep 13. doi: 10.1200/JCO.2018.79.0642).

“We think that’s where this is going to end up, so we think that, if someone starts producing this for a couple hundred thousand bucks, then – certainly in Europe – it will make sense for this to start drifting up and being used as a substitute [to transplant],” he added.

Mr. Schulthess was one of scores of experts and investigators who presented at the EHA/EBMT joint meeting, which included numerous U.S. pioneers in the field and young European investigators, among others, Dr. Chabannon said.

Attesting to the enthusiasm in Europe regarding CAR T, Dr. Chabannon said that there were “more requests for registration than the venue could safely accommodate, a long waiting list, and a high number of individuals on the waiting list who registered for the live streaming” of the event.

“The field of CAR T cells is growing at a fast pace since the first clinical successes reported in the early 2010s, and one can wonder whether the expectations are not in excess of what reality will deliver,” he said. “Nevertheless, CAR T cells represent an essential innovation, not an incremental progress in biomedical sciences. They combine new mechanisms of action, clinical activity in advanced malignancies (and possibly beyond the field of cancer), transfer of manufacturing of human cell-based therapeutics to the industry, and potentially the first commercial success for a gene therapy.”

Surveys conducted by various professional associations, including EBMT, have clearly identified the potential for clinical successes that CAR T cells represent and the tremendous challenges raised by these innovations, he said, noting that “these include fulfilling specific educational needs.”

Therefore, EBMT and EHA have already announced that a second edition of the meeting is planned for Jan. 30 – Feb. 1, 2020, he noted.

Mr. Schulthess reported that his research was funded by the Dutch government.

[email protected]

HOUSTON – With a median follow-up now exceeding 2 years, 39% of refractory large B-cell lymphoma patients enrolled in the pivotal ZUMA-1 trial have maintained ongoing response to axicabtagene ciloleucel, according to an investigator involved in the study.

Mary Jo M. Dales/MDedge News

SOURCE: Neelapu SS et al. TCT 2019, Abstract 82.

HOUSTON – With a median follow-up now exceeding 2 years, 39% of refractory large B-cell lymphoma patients enrolled in the pivotal ZUMA-1 trial have maintained ongoing response to axicabtagene ciloleucel, according to an investigator involved in the study.

Mary Jo M. Dales/MDedge News

SOURCE: Neelapu SS et al. TCT 2019, Abstract 82.

HOUSTON – With a median follow-up now exceeding 2 years, 39% of refractory large B-cell lymphoma patients enrolled in the pivotal ZUMA-1 trial have maintained ongoing response to axicabtagene ciloleucel, according to an investigator involved in the study.

Mary Jo M. Dales/MDedge News

SOURCE: Neelapu SS et al. TCT 2019, Abstract 82.

HOUSTON – A dual-targeted, locally manufactured, anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy was safe and produced ongoing complete responses in a phase 1 study of heavily pretreated non-Hodgkin lymphoma patients, an investigator reported.

Andrew D. Bowser/MDedge News

“So far, this trial has demonstrated safety for this bispecific vector and suggests a clinical signal, with 7 out of 12 patients with ongoing CR, and with minimal toxicity,” Dr. Hari said at the Transplantation & Cellular Therapy Meetings.

“Point of care delivery, we think, allowed patients to have fresh infusion of CAR T cells, with the avoidance of cryopreservation,” added Dr. Hari, who presented the results on behalf of coinvestigators at the Medical College of Wisconsin and Lentigen Technology.

There was no grade 3 or 4 neurotoxicity or cytokine release syndrome among the 12 patients reported to date in the phase 1, dose-escalation trial, and no patient required intensive care, according to Dr. Hari. Grade 1 and 2 neurotoxicity occurred in two and one patients, respectively, while grade 1 and 2 cytokine release syndrome was observed in three patients each.

Among the 12 patients treated to date, the overall response rate was 81% at day 28, Dr. Hari said, noting that of 6 patients treated at the goal dose of 2.5 x 10⁶ cells/kg, 5 remain in ongoing complete remission.

SOURCE: Shah NN et al. TCT 2019, Abstract 80.

HOUSTON – A dual-targeted, locally manufactured, anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy was safe and produced ongoing complete responses in a phase 1 study of heavily pretreated non-Hodgkin lymphoma patients, an investigator reported.

Andrew D. Bowser/MDedge News

“So far, this trial has demonstrated safety for this bispecific vector and suggests a clinical signal, with 7 out of 12 patients with ongoing CR, and with minimal toxicity,” Dr. Hari said at the Transplantation & Cellular Therapy Meetings.

“Point of care delivery, we think, allowed patients to have fresh infusion of CAR T cells, with the avoidance of cryopreservation,” added Dr. Hari, who presented the results on behalf of coinvestigators at the Medical College of Wisconsin and Lentigen Technology.

There was no grade 3 or 4 neurotoxicity or cytokine release syndrome among the 12 patients reported to date in the phase 1, dose-escalation trial, and no patient required intensive care, according to Dr. Hari. Grade 1 and 2 neurotoxicity occurred in two and one patients, respectively, while grade 1 and 2 cytokine release syndrome was observed in three patients each.

Among the 12 patients treated to date, the overall response rate was 81% at day 28, Dr. Hari said, noting that of 6 patients treated at the goal dose of 2.5 x 10⁶ cells/kg, 5 remain in ongoing complete remission.

SOURCE: Shah NN et al. TCT 2019, Abstract 80.

HOUSTON – A dual-targeted, locally manufactured, anti-CD19/CD20 chimeric antigen receptor (CAR) T-cell therapy was safe and produced ongoing complete responses in a phase 1 study of heavily pretreated non-Hodgkin lymphoma patients, an investigator reported.

Andrew D. Bowser/MDedge News

“So far, this trial has demonstrated safety for this bispecific vector and suggests a clinical signal, with 7 out of 12 patients with ongoing CR, and with minimal toxicity,” Dr. Hari said at the Transplantation & Cellular Therapy Meetings.

“Point of care delivery, we think, allowed patients to have fresh infusion of CAR T cells, with the avoidance of cryopreservation,” added Dr. Hari, who presented the results on behalf of coinvestigators at the Medical College of Wisconsin and Lentigen Technology.

There was no grade 3 or 4 neurotoxicity or cytokine release syndrome among the 12 patients reported to date in the phase 1, dose-escalation trial, and no patient required intensive care, according to Dr. Hari. Grade 1 and 2 neurotoxicity occurred in two and one patients, respectively, while grade 1 and 2 cytokine release syndrome was observed in three patients each.

Among the 12 patients treated to date, the overall response rate was 81% at day 28, Dr. Hari said, noting that of 6 patients treated at the goal dose of 2.5 x 10⁶ cells/kg, 5 remain in ongoing complete remission.

SOURCE: Shah NN et al. TCT 2019, Abstract 80.

For patients with diffuse large B-cell lymphoma (DLBCL) who need allogeneic hematopoietic cell transplantation (allo-HCT), a haploidentical family member could be a viable donor, according to a retrospective study of 1,438 patients.

Nephron/Wikimedia Commons/CC BY-SA 3.0

When combined with nonmyeloablative/reduced intensity conditioning (NMC/RIC) and posttransplant cyclophosphamide (PTCy), patients treated with haploidentical HCT (haplo-HCT) had outcomes similar to those seen in patients with matched donors, reported Peter Dreger, MD, of the University of Heidelberg (Germany) and his colleagues.

“Using well-matched sibling donors (MSDs) or unrelated donors (MUDs), allo-HCT can result in sustained disease control in 30% to 45% of patients with DLBCL who have early disease recurrence after standard chemoimmunotherapy or have failed auto-HCT [autologous HCT],” the investigators wrote in Blood Advances. “However, the search for a well-matched unrelated donor could be time-consuming and unsuccessful in up to 50% of the patients in need.”

But the present findings suggest that haplo-HCT may one day improve these odds by providing a larger pool of potential donors.

The patients in the study were divided into four treatment groups: haplo-HCT (n = 132), MSD (n = 525), MUD with T-cell depletion (n = 403), and MUD without T-cell depletion (n = 378). For graft-versus-host disease (GVHD) prophylaxis, patients in the haplo-HCT group received PTCy, with or without a calcineurin inhibitor and mycophenolate mofetil, whereas all patients with matched donors received a calcineurin inhibitor. T-cell depletion was accomplished by in vivo antithymocyte globulin and alemtuzumab.

The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), progression/relapse, and nonrelapse mortality (NRM).

After a median follow-up of 4.1 years, all groups had similar outcomes, without statistical differences in multivariable analysis.

In the haplo-HCT group, the 3-year OS rate was 46%, the NRM rate was 22%, the PFS rate was 38%, and the relapse/progression rate was 41%.

Of note, patients receiving haplo-HCT did have a lower cumulative incidence of chronic GVHD, at 15% after 1 year and 18% after 2 years. These rates were significantly lower than the other groups’ 1- and 2-year GVHD rates, which were as follows: MSD, 41% and 48%; MUD with T-cell depletion, 23% and 27%; and MUD without T-cell depletion, 48% and 57%.

The investigators noted that these disparities may actually be caused by the use of bone marrow grafts in the haplo-HCT group instead of peripheral blood grafts, which were used in most of the patients in the other groups.

Overall, the findings were encouraging, but the investigators cautioned that “additional studies are needed before haploidentical donors can be considered as equivalent to well-matched related or unrelated donors in patients with DLBCL.”

The study was funded by the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation. CIBMTR is supported by grants from the U.S. government and the pharmaceutical industry. The authors reported having no competing financial interests.

SOURCE: Dreger P et al. Blood Adv. 2019 Feb 12;3(3):360-9.

For patients with diffuse large B-cell lymphoma (DLBCL) who need allogeneic hematopoietic cell transplantation (allo-HCT), a haploidentical family member could be a viable donor, according to a retrospective study of 1,438 patients.

Nephron/Wikimedia Commons/CC BY-SA 3.0

When combined with nonmyeloablative/reduced intensity conditioning (NMC/RIC) and posttransplant cyclophosphamide (PTCy), patients treated with haploidentical HCT (haplo-HCT) had outcomes similar to those seen in patients with matched donors, reported Peter Dreger, MD, of the University of Heidelberg (Germany) and his colleagues.

“Using well-matched sibling donors (MSDs) or unrelated donors (MUDs), allo-HCT can result in sustained disease control in 30% to 45% of patients with DLBCL who have early disease recurrence after standard chemoimmunotherapy or have failed auto-HCT [autologous HCT],” the investigators wrote in Blood Advances. “However, the search for a well-matched unrelated donor could be time-consuming and unsuccessful in up to 50% of the patients in need.”

But the present findings suggest that haplo-HCT may one day improve these odds by providing a larger pool of potential donors.

The patients in the study were divided into four treatment groups: haplo-HCT (n = 132), MSD (n = 525), MUD with T-cell depletion (n = 403), and MUD without T-cell depletion (n = 378). For graft-versus-host disease (GVHD) prophylaxis, patients in the haplo-HCT group received PTCy, with or without a calcineurin inhibitor and mycophenolate mofetil, whereas all patients with matched donors received a calcineurin inhibitor. T-cell depletion was accomplished by in vivo antithymocyte globulin and alemtuzumab.

The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), progression/relapse, and nonrelapse mortality (NRM).

After a median follow-up of 4.1 years, all groups had similar outcomes, without statistical differences in multivariable analysis.

In the haplo-HCT group, the 3-year OS rate was 46%, the NRM rate was 22%, the PFS rate was 38%, and the relapse/progression rate was 41%.

Of note, patients receiving haplo-HCT did have a lower cumulative incidence of chronic GVHD, at 15% after 1 year and 18% after 2 years. These rates were significantly lower than the other groups’ 1- and 2-year GVHD rates, which were as follows: MSD, 41% and 48%; MUD with T-cell depletion, 23% and 27%; and MUD without T-cell depletion, 48% and 57%.

The investigators noted that these disparities may actually be caused by the use of bone marrow grafts in the haplo-HCT group instead of peripheral blood grafts, which were used in most of the patients in the other groups.

Overall, the findings were encouraging, but the investigators cautioned that “additional studies are needed before haploidentical donors can be considered as equivalent to well-matched related or unrelated donors in patients with DLBCL.”

The study was funded by the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation. CIBMTR is supported by grants from the U.S. government and the pharmaceutical industry. The authors reported having no competing financial interests.

SOURCE: Dreger P et al. Blood Adv. 2019 Feb 12;3(3):360-9.

For patients with diffuse large B-cell lymphoma (DLBCL) who need allogeneic hematopoietic cell transplantation (allo-HCT), a haploidentical family member could be a viable donor, according to a retrospective study of 1,438 patients.

Nephron/Wikimedia Commons/CC BY-SA 3.0

When combined with nonmyeloablative/reduced intensity conditioning (NMC/RIC) and posttransplant cyclophosphamide (PTCy), patients treated with haploidentical HCT (haplo-HCT) had outcomes similar to those seen in patients with matched donors, reported Peter Dreger, MD, of the University of Heidelberg (Germany) and his colleagues.

“Using well-matched sibling donors (MSDs) or unrelated donors (MUDs), allo-HCT can result in sustained disease control in 30% to 45% of patients with DLBCL who have early disease recurrence after standard chemoimmunotherapy or have failed auto-HCT [autologous HCT],” the investigators wrote in Blood Advances. “However, the search for a well-matched unrelated donor could be time-consuming and unsuccessful in up to 50% of the patients in need.”

But the present findings suggest that haplo-HCT may one day improve these odds by providing a larger pool of potential donors.

The patients in the study were divided into four treatment groups: haplo-HCT (n = 132), MSD (n = 525), MUD with T-cell depletion (n = 403), and MUD without T-cell depletion (n = 378). For graft-versus-host disease (GVHD) prophylaxis, patients in the haplo-HCT group received PTCy, with or without a calcineurin inhibitor and mycophenolate mofetil, whereas all patients with matched donors received a calcineurin inhibitor. T-cell depletion was accomplished by in vivo antithymocyte globulin and alemtuzumab.

The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), progression/relapse, and nonrelapse mortality (NRM).

After a median follow-up of 4.1 years, all groups had similar outcomes, without statistical differences in multivariable analysis.

In the haplo-HCT group, the 3-year OS rate was 46%, the NRM rate was 22%, the PFS rate was 38%, and the relapse/progression rate was 41%.

Of note, patients receiving haplo-HCT did have a lower cumulative incidence of chronic GVHD, at 15% after 1 year and 18% after 2 years. These rates were significantly lower than the other groups’ 1- and 2-year GVHD rates, which were as follows: MSD, 41% and 48%; MUD with T-cell depletion, 23% and 27%; and MUD without T-cell depletion, 48% and 57%.

The investigators noted that these disparities may actually be caused by the use of bone marrow grafts in the haplo-HCT group instead of peripheral blood grafts, which were used in most of the patients in the other groups.

Overall, the findings were encouraging, but the investigators cautioned that “additional studies are needed before haploidentical donors can be considered as equivalent to well-matched related or unrelated donors in patients with DLBCL.”

The study was funded by the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation. CIBMTR is supported by grants from the U.S. government and the pharmaceutical industry. The authors reported having no competing financial interests.

SOURCE: Dreger P et al. Blood Adv. 2019 Feb 12;3(3):360-9.

The Food and Drug Administration (FDA) has granted priority review to a biologics license application (BLA) for polatuzumab vedotin, an anti-CD79b antibody drug conjugate.

With this BLA, Genentech is seeking approval for polatuzumab vedotin in combination with bendamustine and rituximab (BR) to treat patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency aims to take action on a priority review application within 6 months, rather than the standard 10 months.

The FDA is expected to make a decision on this BLA by Aug. 19, 2019.

The BLA is supported by a phase 1b/2 trial (NCT02257567) of patients with relapsed or refractory follicular lymphoma or DLBCL who received polatuzumab vedotin in combination with BR or obinutuzumab.

The trial’s phase 2 stage included 80 DLBCL patients who were randomized to receive BR or BR plus polatuzumab vedotin, according to Genentech.

The complete response rate was 40% in the polatuzumab vedotin arm and 18% in the BR arm. The median duration of response was 10.3 months and 4.1 months, respectively (hazard ratio [HR] = 0.44).

The median progression-free survival was 7.6 months in the polatuzumab vedotin arm and 2.0 months in the BR arm (HR = 0.34).

Among patients who were ineligible for a transplant, the median overall survival (an exploratory endpoint) was 12.4 months in the polatuzumab vedotin arm and 4.7 months in the BR arm (HR = 0.42).

Patients who received polatuzumab vedotin had higher rates of grade 3-4 cytopenias, compared with patients who received BR alone. Rates of infection and transfusion were similar between the arms.

[email protected]

The Food and Drug Administration (FDA) has granted priority review to a biologics license application (BLA) for polatuzumab vedotin, an anti-CD79b antibody drug conjugate.

With this BLA, Genentech is seeking approval for polatuzumab vedotin in combination with bendamustine and rituximab (BR) to treat patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency aims to take action on a priority review application within 6 months, rather than the standard 10 months.

The FDA is expected to make a decision on this BLA by Aug. 19, 2019.

The BLA is supported by a phase 1b/2 trial (NCT02257567) of patients with relapsed or refractory follicular lymphoma or DLBCL who received polatuzumab vedotin in combination with BR or obinutuzumab.

The trial’s phase 2 stage included 80 DLBCL patients who were randomized to receive BR or BR plus polatuzumab vedotin, according to Genentech.

The complete response rate was 40% in the polatuzumab vedotin arm and 18% in the BR arm. The median duration of response was 10.3 months and 4.1 months, respectively (hazard ratio [HR] = 0.44).

The median progression-free survival was 7.6 months in the polatuzumab vedotin arm and 2.0 months in the BR arm (HR = 0.34).

Among patients who were ineligible for a transplant, the median overall survival (an exploratory endpoint) was 12.4 months in the polatuzumab vedotin arm and 4.7 months in the BR arm (HR = 0.42).

Patients who received polatuzumab vedotin had higher rates of grade 3-4 cytopenias, compared with patients who received BR alone. Rates of infection and transfusion were similar between the arms.

[email protected]

The Food and Drug Administration (FDA) has granted priority review to a biologics license application (BLA) for polatuzumab vedotin, an anti-CD79b antibody drug conjugate.

With this BLA, Genentech is seeking approval for polatuzumab vedotin in combination with bendamustine and rituximab (BR) to treat patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

The FDA grants priority review to applications for products that are expected to provide significant improvements in the treatment, diagnosis, or prevention of serious conditions. The agency aims to take action on a priority review application within 6 months, rather than the standard 10 months.

The FDA is expected to make a decision on this BLA by Aug. 19, 2019.

The BLA is supported by a phase 1b/2 trial (NCT02257567) of patients with relapsed or refractory follicular lymphoma or DLBCL who received polatuzumab vedotin in combination with BR or obinutuzumab.

The trial’s phase 2 stage included 80 DLBCL patients who were randomized to receive BR or BR plus polatuzumab vedotin, according to Genentech.

The complete response rate was 40% in the polatuzumab vedotin arm and 18% in the BR arm. The median duration of response was 10.3 months and 4.1 months, respectively (hazard ratio [HR] = 0.44).

The median progression-free survival was 7.6 months in the polatuzumab vedotin arm and 2.0 months in the BR arm (HR = 0.34).

Among patients who were ineligible for a transplant, the median overall survival (an exploratory endpoint) was 12.4 months in the polatuzumab vedotin arm and 4.7 months in the BR arm (HR = 0.42).

Patients who received polatuzumab vedotin had higher rates of grade 3-4 cytopenias, compared with patients who received BR alone. Rates of infection and transfusion were similar between the arms.

[email protected]

Researchers say they have characterized a subtype of diffuse large B-cell lymphoma (DLBCL) with distinct molecular features and poor prognosis.

Patients with this subtype, dubbed “molecular high-grade” (MHG) DLBCL, were more likely to have germinal center B-cell-like (GCB) DLBCL, MYC rearrangements, and double-hit lymphoma.

When compared to other DLBCL patients, those with MHG DLBCL had inferior progression-free and overall survival.

Chulin Sha, PhD, of the University of Leeds (England), and colleagues reported these findings in the Journal of Clinical Oncology. The findings were published alongside a related editorial and a similar study from another group.

Dr. Sha and colleagues began their study by applying a previously developed gene expression classifier (Genome Med. 2015 Jul 1;7[1]:64) to 928 DLBCL patients enrolled in the REMoDL-B trial. REMoDL-B was designed to compare rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to R-CHOP plus bortezomib (Hematol Oncol. 2017;35:130-1).

Dr. Sha and colleagues looked for somatic mutations in 400 REMoDL-B patient samples that were sequenced for a 70-gene panel.

The team also tested 360 samples for MYC, BCL2, and BCL6 chromosomal rearrangements using fluorescent in situ hybridization, and they tested 355 samples for MYC and BCL2 protein expression with immunohistochemistry.

Characteristics of MHG DLBCL

The researchers identified 83 REMoDL-B patients as having MHG DLBCL (9%). Most of the MHG patients had GCB DLBCL (90%), 48.6% had MYC rearrangements, and 36.1% had double-hit lymphoma.

Patients with MHG DLBCL had higher International Prognostic Index scores (P = .004), greater tumor bulk (P = .007), higher disease stage (P = .06), and higher lactate dehydrogenase levels (P less than .001) than patients with non-MHG DLBCL.

Although most MHG patients had GCB DLBCL, the researchers found key differences between patients with MHG DLBCL and non-MHG GCB DLBCL. MHG patients were significantly more likely than patients with non-MHG GCB DLBCL to have mutations in KMT2D, BCL2, MYC, and DDX3X. Additionally, some genes frequently mutated in GCB DLBCL — such as B2M, SGK1, and NFKBIA — were rare in MHG DLBCL.

Dr. Sha and colleagues also compared the MHG patients to 70 patients with Burkitt lymphoma (BL) who had been analyzed in a previous study (Genome Med. 2015 Jul 1;7[1]:64).

The researchers found that BL has more upregulated genes than GCB (2,483 genes) and MHG DLBCL (1,784 genes), and MHG DLBCL has more upregulated genes than GCB DLBCL (382 genes). The team observed a similar pattern with downregulated genes and said this suggests “MHG is an intermediate group but closer to GCB than to BL.”

• 37% for MHG patients
• 78% for patients with GCB DLBCL
• 64% for patients with activated B-cell like (ABC) DLBCL
• 65% for patients with unclassified DLBCL.

Among patients who received bortezomib plus R-CHOP, there was a trend toward improved PFS for patients with MHG DLBCL (58%; P = .08).

Validation cohort

Dr. Sha and colleagues validated their initial findings using RNA sequencing data from another group of DLBCL patients (Cell. 2017 Oct 5;171[2]:481-94.e15). This data set included 624 patients who received rituximab-based therapy.

Seventy-two patients in this group had MHG DLBCL (11.5%), and most MHG patients had GCB DLBCL (82%).

The researchers said the MHG group in this cohort “showed similar associations with clinical variables” and a “similar mutation spectrum” as the MHG group in the REMoDL-B cohort. Additionally, MHG patients in the validation cohort had inferior overall survival (P less than .001) compared to patients with non-MHG GCB DLBCL.

Dr. Sha and colleagues said the poor prognosis in MHG patients in both cohorts suggests a need for different treatment approaches in this group.

In the related editorial, Wing C. Chan, MD, of City of Hope Medical Center in Duarte, Calif., echoed that sentiment and said it will be important to include patients with high-risk DLBCL in clinical trials.

“Their tumors should be comprehensively characterize[d] for correlative analysis to determine the molecular lesions that underlie their biology and response to treatment,” Dr. Chan wrote.

Dr. Chan disclosed a patent for a diagnostic algorithm on GCB/ABC-type DLBCL and a patent on a diagnostic algorithm for peripheral T-cell lymphoma.

Dr. Sha and colleagues disclosed relationships with a range of pharmaceutical companies. The team’s research was supported by a grant from Bloodwise.

The REMoDL-B trial was endorsed by Cancer Research UK and was funded by Janssen-Cillag.

[email protected]

SOURCES: Sha C et al. J Clin Oncol. 2019 Jan 20;37(3):202-12. doi: 10.1200/JCO.18.01314; Chan WC. J Clin Oncol. 2019 Jan 20;37(3):175-7. doi: 10.1200/JCO.18.01910; Ennishi D et al. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583

Researchers say they have characterized a subtype of diffuse large B-cell lymphoma (DLBCL) with distinct molecular features and poor prognosis.

Patients with this subtype, dubbed “molecular high-grade” (MHG) DLBCL, were more likely to have germinal center B-cell-like (GCB) DLBCL, MYC rearrangements, and double-hit lymphoma.

When compared to other DLBCL patients, those with MHG DLBCL had inferior progression-free and overall survival.

Chulin Sha, PhD, of the University of Leeds (England), and colleagues reported these findings in the Journal of Clinical Oncology. The findings were published alongside a related editorial and a similar study from another group.

Dr. Sha and colleagues began their study by applying a previously developed gene expression classifier (Genome Med. 2015 Jul 1;7[1]:64) to 928 DLBCL patients enrolled in the REMoDL-B trial. REMoDL-B was designed to compare rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to R-CHOP plus bortezomib (Hematol Oncol. 2017;35:130-1).

Dr. Sha and colleagues looked for somatic mutations in 400 REMoDL-B patient samples that were sequenced for a 70-gene panel.

The team also tested 360 samples for MYC, BCL2, and BCL6 chromosomal rearrangements using fluorescent in situ hybridization, and they tested 355 samples for MYC and BCL2 protein expression with immunohistochemistry.

Characteristics of MHG DLBCL

The researchers identified 83 REMoDL-B patients as having MHG DLBCL (9%). Most of the MHG patients had GCB DLBCL (90%), 48.6% had MYC rearrangements, and 36.1% had double-hit lymphoma.

Patients with MHG DLBCL had higher International Prognostic Index scores (P = .004), greater tumor bulk (P = .007), higher disease stage (P = .06), and higher lactate dehydrogenase levels (P less than .001) than patients with non-MHG DLBCL.

Although most MHG patients had GCB DLBCL, the researchers found key differences between patients with MHG DLBCL and non-MHG GCB DLBCL. MHG patients were significantly more likely than patients with non-MHG GCB DLBCL to have mutations in KMT2D, BCL2, MYC, and DDX3X. Additionally, some genes frequently mutated in GCB DLBCL — such as B2M, SGK1, and NFKBIA — were rare in MHG DLBCL.

Dr. Sha and colleagues also compared the MHG patients to 70 patients with Burkitt lymphoma (BL) who had been analyzed in a previous study (Genome Med. 2015 Jul 1;7[1]:64).

The researchers found that BL has more upregulated genes than GCB (2,483 genes) and MHG DLBCL (1,784 genes), and MHG DLBCL has more upregulated genes than GCB DLBCL (382 genes). The team observed a similar pattern with downregulated genes and said this suggests “MHG is an intermediate group but closer to GCB than to BL.”

• 37% for MHG patients
• 78% for patients with GCB DLBCL
• 64% for patients with activated B-cell like (ABC) DLBCL
• 65% for patients with unclassified DLBCL.

Among patients who received bortezomib plus R-CHOP, there was a trend toward improved PFS for patients with MHG DLBCL (58%; P = .08).

Validation cohort

Dr. Sha and colleagues validated their initial findings using RNA sequencing data from another group of DLBCL patients (Cell. 2017 Oct 5;171[2]:481-94.e15). This data set included 624 patients who received rituximab-based therapy.

Seventy-two patients in this group had MHG DLBCL (11.5%), and most MHG patients had GCB DLBCL (82%).

The researchers said the MHG group in this cohort “showed similar associations with clinical variables” and a “similar mutation spectrum” as the MHG group in the REMoDL-B cohort. Additionally, MHG patients in the validation cohort had inferior overall survival (P less than .001) compared to patients with non-MHG GCB DLBCL.

Dr. Sha and colleagues said the poor prognosis in MHG patients in both cohorts suggests a need for different treatment approaches in this group.

In the related editorial, Wing C. Chan, MD, of City of Hope Medical Center in Duarte, Calif., echoed that sentiment and said it will be important to include patients with high-risk DLBCL in clinical trials.

“Their tumors should be comprehensively characterize[d] for correlative analysis to determine the molecular lesions that underlie their biology and response to treatment,” Dr. Chan wrote.

Dr. Chan disclosed a patent for a diagnostic algorithm on GCB/ABC-type DLBCL and a patent on a diagnostic algorithm for peripheral T-cell lymphoma.

Dr. Sha and colleagues disclosed relationships with a range of pharmaceutical companies. The team’s research was supported by a grant from Bloodwise.

The REMoDL-B trial was endorsed by Cancer Research UK and was funded by Janssen-Cillag.

[email protected]

SOURCES: Sha C et al. J Clin Oncol. 2019 Jan 20;37(3):202-12. doi: 10.1200/JCO.18.01314; Chan WC. J Clin Oncol. 2019 Jan 20;37(3):175-7. doi: 10.1200/JCO.18.01910; Ennishi D et al. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583

Researchers say they have characterized a subtype of diffuse large B-cell lymphoma (DLBCL) with distinct molecular features and poor prognosis.

Patients with this subtype, dubbed “molecular high-grade” (MHG) DLBCL, were more likely to have germinal center B-cell-like (GCB) DLBCL, MYC rearrangements, and double-hit lymphoma.

When compared to other DLBCL patients, those with MHG DLBCL had inferior progression-free and overall survival.

Chulin Sha, PhD, of the University of Leeds (England), and colleagues reported these findings in the Journal of Clinical Oncology. The findings were published alongside a related editorial and a similar study from another group.

Dr. Sha and colleagues began their study by applying a previously developed gene expression classifier (Genome Med. 2015 Jul 1;7[1]:64) to 928 DLBCL patients enrolled in the REMoDL-B trial. REMoDL-B was designed to compare rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) to R-CHOP plus bortezomib (Hematol Oncol. 2017;35:130-1).

Dr. Sha and colleagues looked for somatic mutations in 400 REMoDL-B patient samples that were sequenced for a 70-gene panel.

The team also tested 360 samples for MYC, BCL2, and BCL6 chromosomal rearrangements using fluorescent in situ hybridization, and they tested 355 samples for MYC and BCL2 protein expression with immunohistochemistry.

Characteristics of MHG DLBCL

The researchers identified 83 REMoDL-B patients as having MHG DLBCL (9%). Most of the MHG patients had GCB DLBCL (90%), 48.6% had MYC rearrangements, and 36.1% had double-hit lymphoma.

Patients with MHG DLBCL had higher International Prognostic Index scores (P = .004), greater tumor bulk (P = .007), higher disease stage (P = .06), and higher lactate dehydrogenase levels (P less than .001) than patients with non-MHG DLBCL.

Although most MHG patients had GCB DLBCL, the researchers found key differences between patients with MHG DLBCL and non-MHG GCB DLBCL. MHG patients were significantly more likely than patients with non-MHG GCB DLBCL to have mutations in KMT2D, BCL2, MYC, and DDX3X. Additionally, some genes frequently mutated in GCB DLBCL — such as B2M, SGK1, and NFKBIA — were rare in MHG DLBCL.

Dr. Sha and colleagues also compared the MHG patients to 70 patients with Burkitt lymphoma (BL) who had been analyzed in a previous study (Genome Med. 2015 Jul 1;7[1]:64).

The researchers found that BL has more upregulated genes than GCB (2,483 genes) and MHG DLBCL (1,784 genes), and MHG DLBCL has more upregulated genes than GCB DLBCL (382 genes). The team observed a similar pattern with downregulated genes and said this suggests “MHG is an intermediate group but closer to GCB than to BL.”

• 37% for MHG patients
• 78% for patients with GCB DLBCL
• 64% for patients with activated B-cell like (ABC) DLBCL
• 65% for patients with unclassified DLBCL.

Among patients who received bortezomib plus R-CHOP, there was a trend toward improved PFS for patients with MHG DLBCL (58%; P = .08).

Validation cohort

Dr. Sha and colleagues validated their initial findings using RNA sequencing data from another group of DLBCL patients (Cell. 2017 Oct 5;171[2]:481-94.e15). This data set included 624 patients who received rituximab-based therapy.

Seventy-two patients in this group had MHG DLBCL (11.5%), and most MHG patients had GCB DLBCL (82%).

The researchers said the MHG group in this cohort “showed similar associations with clinical variables” and a “similar mutation spectrum” as the MHG group in the REMoDL-B cohort. Additionally, MHG patients in the validation cohort had inferior overall survival (P less than .001) compared to patients with non-MHG GCB DLBCL.

Dr. Sha and colleagues said the poor prognosis in MHG patients in both cohorts suggests a need for different treatment approaches in this group.

In the related editorial, Wing C. Chan, MD, of City of Hope Medical Center in Duarte, Calif., echoed that sentiment and said it will be important to include patients with high-risk DLBCL in clinical trials.

“Their tumors should be comprehensively characterize[d] for correlative analysis to determine the molecular lesions that underlie their biology and response to treatment,” Dr. Chan wrote.

Dr. Chan disclosed a patent for a diagnostic algorithm on GCB/ABC-type DLBCL and a patent on a diagnostic algorithm for peripheral T-cell lymphoma.

Dr. Sha and colleagues disclosed relationships with a range of pharmaceutical companies. The team’s research was supported by a grant from Bloodwise.

The REMoDL-B trial was endorsed by Cancer Research UK and was funded by Janssen-Cillag.

[email protected]

SOURCES: Sha C et al. J Clin Oncol. 2019 Jan 20;37(3):202-12. doi: 10.1200/JCO.18.01314; Chan WC. J Clin Oncol. 2019 Jan 20;37(3):175-7. doi: 10.1200/JCO.18.01910; Ennishi D et al. J Clin Oncol. 2019 Jan 20;37(3):190-201. doi: 10.1200/JCO.18.01583

One chimeric antigen receptor (CAR) T-cell therapy may appear better than another, but confounding factors make it difficult to compare these therapies effectively, according to a review published in the Journal of Clinical Oncology.

Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, reviewed results from three trials of CAR T-cell therapies in patients with B-cell non-Hodgkin lymphoma (B-NHL).

She noted that cross-trial comparisons are always limited, but such comparisons of CAR T-cell therapies are hindered by several confounding factors.

Dr. Jacobson said differences in manufacturing procedures and turnaround time, differences in patient eligibility and management, and the complexity of CAR T-cell therapies make it difficult to compare results from three CAR-T trials in B-NHL:

• The ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel, Yescarta)
• The JULIET trial (NCT02445248) of tisagenlecleucel (t-cel, Kymriah)
• The TRANSCEND-NHL-001 trial (NCT02631044) of lisocabtagene maraleucel (liso-cel, JCAR017).

Looking at response rates alone, axi-cel appears the most promising. The overall response rate (ORR) was 82% with axi-cel, 75% with liso-cel, and 52% with t-cel.

When considering cytokine release syndrome (CRS), liso-cel appears the safest. The rate of CRS was 93% with axi-cel (13% grade 3 or higher), 58% with t-cel (22% grade 3 or higher), and 39% with liso-cel (1% grade 3 or higher).

However, as Dr. Jacobson pointed out, it’s impossible to know if these differences in efficacy and toxicity are “statistically meaningful.”

[email protected]

SOURCE: Jacobson CA. J Clin Oncol. 2019 Feb 1;37(4):328-35. doi: 10.1200/JCO.18.01457

One chimeric antigen receptor (CAR) T-cell therapy may appear better than another, but confounding factors make it difficult to compare these therapies effectively, according to a review published in the Journal of Clinical Oncology.

Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, reviewed results from three trials of CAR T-cell therapies in patients with B-cell non-Hodgkin lymphoma (B-NHL).

She noted that cross-trial comparisons are always limited, but such comparisons of CAR T-cell therapies are hindered by several confounding factors.

Dr. Jacobson said differences in manufacturing procedures and turnaround time, differences in patient eligibility and management, and the complexity of CAR T-cell therapies make it difficult to compare results from three CAR-T trials in B-NHL:

• The ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel, Yescarta)
• The JULIET trial (NCT02445248) of tisagenlecleucel (t-cel, Kymriah)
• The TRANSCEND-NHL-001 trial (NCT02631044) of lisocabtagene maraleucel (liso-cel, JCAR017).

Looking at response rates alone, axi-cel appears the most promising. The overall response rate (ORR) was 82% with axi-cel, 75% with liso-cel, and 52% with t-cel.

When considering cytokine release syndrome (CRS), liso-cel appears the safest. The rate of CRS was 93% with axi-cel (13% grade 3 or higher), 58% with t-cel (22% grade 3 or higher), and 39% with liso-cel (1% grade 3 or higher).

However, as Dr. Jacobson pointed out, it’s impossible to know if these differences in efficacy and toxicity are “statistically meaningful.”

[email protected]

SOURCE: Jacobson CA. J Clin Oncol. 2019 Feb 1;37(4):328-35. doi: 10.1200/JCO.18.01457

One chimeric antigen receptor (CAR) T-cell therapy may appear better than another, but confounding factors make it difficult to compare these therapies effectively, according to a review published in the Journal of Clinical Oncology.

Caron A. Jacobson, MD, of the Dana-Farber Cancer Institute in Boston, reviewed results from three trials of CAR T-cell therapies in patients with B-cell non-Hodgkin lymphoma (B-NHL).

She noted that cross-trial comparisons are always limited, but such comparisons of CAR T-cell therapies are hindered by several confounding factors.

Dr. Jacobson said differences in manufacturing procedures and turnaround time, differences in patient eligibility and management, and the complexity of CAR T-cell therapies make it difficult to compare results from three CAR-T trials in B-NHL:

• The ZUMA-1 trial (NCT02348216) of axicabtagene ciloleucel (axi-cel, Yescarta)
• The JULIET trial (NCT02445248) of tisagenlecleucel (t-cel, Kymriah)
• The TRANSCEND-NHL-001 trial (NCT02631044) of lisocabtagene maraleucel (liso-cel, JCAR017).

Looking at response rates alone, axi-cel appears the most promising. The overall response rate (ORR) was 82% with axi-cel, 75% with liso-cel, and 52% with t-cel.

When considering cytokine release syndrome (CRS), liso-cel appears the safest. The rate of CRS was 93% with axi-cel (13% grade 3 or higher), 58% with t-cel (22% grade 3 or higher), and 39% with liso-cel (1% grade 3 or higher).

However, as Dr. Jacobson pointed out, it’s impossible to know if these differences in efficacy and toxicity are “statistically meaningful.”

[email protected]

SOURCE: Jacobson CA. J Clin Oncol. 2019 Feb 1;37(4):328-35. doi: 10.1200/JCO.18.01457

An early study adding palbociclib to ibrutinib in previously treated patients with mantle cell lymphoma (MCL) showed a higher complete response rate than what has previously been reported for single-agent ibrutinib, according to investigators.

Results from the phase 1 trial (NCT02159755) support preclinical models, suggesting that the CDK4/6 inhibitor palbociclib may be able to help overcome resistance to ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK).

These findings set the stage for an ongoing phase 2 multicenter study, reported lead author Peter Martin, MD, of Weill Cornell Medicine in New York and his colleagues.

The present study involved 27 patients with previously treated MCL, the investigators wrote in Blood. Of these, 21 were men and 6 were women, all of whom had adequate organ and bone marrow function, good performance status, and no previous treatment with CDK4/6 or BTK inhibitors.

Patients were randomly grouped into five dose levels of each drug: Ibrutinib doses ranged from 280-560 mg, and palbociclib from 75-125 mg. Ibrutinib was given daily and palbociclib was administered for 21 out of 28 days per cycle. Therapy continued until withdrawal, unacceptable toxicity, or disease progression.

The primary objective was to determine phase 2 dose. Secondarily, the investigators sought to determine activity and toxicity profiles. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1-21 of each 28-day cycle.

Across all patients, the complete response rate was 37%, compared with 21% for ibrutinib monotherapy in a previous trial. About two-thirds of patients had a response of any kind, which aligns closely with the overall response rate previously reported for ibrutinib alone (67% vs. 68%). After a median follow-up of 25.6 months in survivors, the 2-year progression free survival was 59.4%. The two-year overall survival rate was 60.6%.

The dose-limiting toxicity was grade 3 rash, which occurred in two out of five patients treated at the highest doses. The most common grade 3 or higher toxicities were neutropenia (41%) and thrombocytopenia (30%), followed by hypertension (15%), febrile neutropenia (15%), lung infection (11%), fatigue (7%), upper respiratory tract infection (7%), hyperglycemia (7%), rash (7%), myalgia (7%), and increased alanine transaminase/aspartate aminotransferase (7%).

“Although BTK-inhibitor-based combinations appear promising, the degree to which they improve upon single-agent ibrutinib is unclear,” the investigators wrote, noting that a phase 2 trial (NCT03478514) is currently underway and uses the maximum tolerated doses.

The phase 1 trial was sponsored by the National Cancer Institute. Study funding was provided by the Sarah Cannon Fund at the HCA Foundation. The investigators reported financial relationships with Janssen, Gilead, AstraZeneca, Celgene, Karyopharm, and others.

SOURCE: Martin P et al. Blood. 2019 Jan 28. doi: 10.1182/blood-2018-11-886457.

An early study adding palbociclib to ibrutinib in previously treated patients with mantle cell lymphoma (MCL) showed a higher complete response rate than what has previously been reported for single-agent ibrutinib, according to investigators.

Results from the phase 1 trial (NCT02159755) support preclinical models, suggesting that the CDK4/6 inhibitor palbociclib may be able to help overcome resistance to ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK).

These findings set the stage for an ongoing phase 2 multicenter study, reported lead author Peter Martin, MD, of Weill Cornell Medicine in New York and his colleagues.

The present study involved 27 patients with previously treated MCL, the investigators wrote in Blood. Of these, 21 were men and 6 were women, all of whom had adequate organ and bone marrow function, good performance status, and no previous treatment with CDK4/6 or BTK inhibitors.

Patients were randomly grouped into five dose levels of each drug: Ibrutinib doses ranged from 280-560 mg, and palbociclib from 75-125 mg. Ibrutinib was given daily and palbociclib was administered for 21 out of 28 days per cycle. Therapy continued until withdrawal, unacceptable toxicity, or disease progression.

The primary objective was to determine phase 2 dose. Secondarily, the investigators sought to determine activity and toxicity profiles. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1-21 of each 28-day cycle.

Across all patients, the complete response rate was 37%, compared with 21% for ibrutinib monotherapy in a previous trial. About two-thirds of patients had a response of any kind, which aligns closely with the overall response rate previously reported for ibrutinib alone (67% vs. 68%). After a median follow-up of 25.6 months in survivors, the 2-year progression free survival was 59.4%. The two-year overall survival rate was 60.6%.

The dose-limiting toxicity was grade 3 rash, which occurred in two out of five patients treated at the highest doses. The most common grade 3 or higher toxicities were neutropenia (41%) and thrombocytopenia (30%), followed by hypertension (15%), febrile neutropenia (15%), lung infection (11%), fatigue (7%), upper respiratory tract infection (7%), hyperglycemia (7%), rash (7%), myalgia (7%), and increased alanine transaminase/aspartate aminotransferase (7%).

“Although BTK-inhibitor-based combinations appear promising, the degree to which they improve upon single-agent ibrutinib is unclear,” the investigators wrote, noting that a phase 2 trial (NCT03478514) is currently underway and uses the maximum tolerated doses.

The phase 1 trial was sponsored by the National Cancer Institute. Study funding was provided by the Sarah Cannon Fund at the HCA Foundation. The investigators reported financial relationships with Janssen, Gilead, AstraZeneca, Celgene, Karyopharm, and others.

SOURCE: Martin P et al. Blood. 2019 Jan 28. doi: 10.1182/blood-2018-11-886457.

An early study adding palbociclib to ibrutinib in previously treated patients with mantle cell lymphoma (MCL) showed a higher complete response rate than what has previously been reported for single-agent ibrutinib, according to investigators.

Results from the phase 1 trial (NCT02159755) support preclinical models, suggesting that the CDK4/6 inhibitor palbociclib may be able to help overcome resistance to ibrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK).

These findings set the stage for an ongoing phase 2 multicenter study, reported lead author Peter Martin, MD, of Weill Cornell Medicine in New York and his colleagues.

The present study involved 27 patients with previously treated MCL, the investigators wrote in Blood. Of these, 21 were men and 6 were women, all of whom had adequate organ and bone marrow function, good performance status, and no previous treatment with CDK4/6 or BTK inhibitors.

Patients were randomly grouped into five dose levels of each drug: Ibrutinib doses ranged from 280-560 mg, and palbociclib from 75-125 mg. Ibrutinib was given daily and palbociclib was administered for 21 out of 28 days per cycle. Therapy continued until withdrawal, unacceptable toxicity, or disease progression.

The primary objective was to determine phase 2 dose. Secondarily, the investigators sought to determine activity and toxicity profiles. The maximum tolerated doses were ibrutinib 560 mg daily plus palbociclib 100 mg on days 1-21 of each 28-day cycle.

Across all patients, the complete response rate was 37%, compared with 21% for ibrutinib monotherapy in a previous trial. About two-thirds of patients had a response of any kind, which aligns closely with the overall response rate previously reported for ibrutinib alone (67% vs. 68%). After a median follow-up of 25.6 months in survivors, the 2-year progression free survival was 59.4%. The two-year overall survival rate was 60.6%.

The dose-limiting toxicity was grade 3 rash, which occurred in two out of five patients treated at the highest doses. The most common grade 3 or higher toxicities were neutropenia (41%) and thrombocytopenia (30%), followed by hypertension (15%), febrile neutropenia (15%), lung infection (11%), fatigue (7%), upper respiratory tract infection (7%), hyperglycemia (7%), rash (7%), myalgia (7%), and increased alanine transaminase/aspartate aminotransferase (7%).

“Although BTK-inhibitor-based combinations appear promising, the degree to which they improve upon single-agent ibrutinib is unclear,” the investigators wrote, noting that a phase 2 trial (NCT03478514) is currently underway and uses the maximum tolerated doses.

The phase 1 trial was sponsored by the National Cancer Institute. Study funding was provided by the Sarah Cannon Fund at the HCA Foundation. The investigators reported financial relationships with Janssen, Gilead, AstraZeneca, Celgene, Karyopharm, and others.

SOURCE: Martin P et al. Blood. 2019 Jan 28. doi: 10.1182/blood-2018-11-886457.