CLL

Nonmyeloablative haploidentical allo-bone marrow transplantation with posttransplantation cyclophosphamide is a safe and effective treatment option for patients with chronic lymphocytic leukemia (CLL), according to a study published in Biology of Blood and Marrow Transplantation.

The number of patients undergoing haploidentical allo-BMT has increased substantially, with the advent of new graft-versus-host disease (GVHD) prophylaxis strategies, such as posttransplantation cyclophosphamide (PTCy), that reduce the risk of GVHD complications; however there have been few studies assessing the results of this treatment regimen, according to the authors.

The study assessed 64 consecutive patients with CLL between Jan. 2005 and Aug. 2018 who underwent haploidentical allo-BMT. The median age was 59 years; 4 patients (6.2%) underwent allo-BMT after first-line treatment; 20 patients (31.2%) underwent allo-BMT after second-line treatment, and 40 patients (62.5%) underwent allo-BMT after three or more lines of treatment for relapsed and/or refractory disease.

All patients received a nonmyeloablative (NMA) conditioning regimen consisting of fludarabine, cyclophosphamide, and 200 cGy total body irradiation. Patients received PTCy (i.v. 50 mg/kg per day) on days +3 and +4, along with additional GVHD prophylaxis with mycophenolate mofetil between days +5 and +35 and tacrolimus or sirolimus between days +5 and +180.

For all 64 patients, the median duration of follow-up was 4.4 years based on the reverse Kaplan-Meier method. The 4-year overall survival (OS) was 52%, and the 4-year progression-free survival (PFS) was 37%. The 56 patients with less than 20% marrow CLL involvement before undergoing allo-BMT had a 4-year OS of 61%, a 4-year PFS of 43%, and a median OS of 4.8 years, according to the authors.

Regression analysis demonstrated that donor age, stem cell source, IGHV mutation status, or grade II-III acute GVHD did not affect risk of progression or survival.

“The majority of our patients had unfavorable risk factors, and collectively our data show that haploidentical allo-BMT with PTCy in CLL with less than 20% marrow involvement is a safe treatment option carrying a low risk of serious GVHD and other toxicities,” the researchers concluded.

The study was supported by National Institutes of Health, National Cancer Institute grants. The authors reported that they had no disclosures.

[email protected]

SOURCE: Suman P et al. Biol Blood Marrow Transplant. 2020 Mar 1;26:502-8. doi: 10.1016/j.bbmt.2019.11.008

Nonmyeloablative haploidentical allo-bone marrow transplantation with posttransplantation cyclophosphamide is a safe and effective treatment option for patients with chronic lymphocytic leukemia (CLL), according to a study published in Biology of Blood and Marrow Transplantation.

The number of patients undergoing haploidentical allo-BMT has increased substantially, with the advent of new graft-versus-host disease (GVHD) prophylaxis strategies, such as posttransplantation cyclophosphamide (PTCy), that reduce the risk of GVHD complications; however there have been few studies assessing the results of this treatment regimen, according to the authors.

The study assessed 64 consecutive patients with CLL between Jan. 2005 and Aug. 2018 who underwent haploidentical allo-BMT. The median age was 59 years; 4 patients (6.2%) underwent allo-BMT after first-line treatment; 20 patients (31.2%) underwent allo-BMT after second-line treatment, and 40 patients (62.5%) underwent allo-BMT after three or more lines of treatment for relapsed and/or refractory disease.

All patients received a nonmyeloablative (NMA) conditioning regimen consisting of fludarabine, cyclophosphamide, and 200 cGy total body irradiation. Patients received PTCy (i.v. 50 mg/kg per day) on days +3 and +4, along with additional GVHD prophylaxis with mycophenolate mofetil between days +5 and +35 and tacrolimus or sirolimus between days +5 and +180.

For all 64 patients, the median duration of follow-up was 4.4 years based on the reverse Kaplan-Meier method. The 4-year overall survival (OS) was 52%, and the 4-year progression-free survival (PFS) was 37%. The 56 patients with less than 20% marrow CLL involvement before undergoing allo-BMT had a 4-year OS of 61%, a 4-year PFS of 43%, and a median OS of 4.8 years, according to the authors.

Regression analysis demonstrated that donor age, stem cell source, IGHV mutation status, or grade II-III acute GVHD did not affect risk of progression or survival.

“The majority of our patients had unfavorable risk factors, and collectively our data show that haploidentical allo-BMT with PTCy in CLL with less than 20% marrow involvement is a safe treatment option carrying a low risk of serious GVHD and other toxicities,” the researchers concluded.

The study was supported by National Institutes of Health, National Cancer Institute grants. The authors reported that they had no disclosures.

[email protected]

SOURCE: Suman P et al. Biol Blood Marrow Transplant. 2020 Mar 1;26:502-8. doi: 10.1016/j.bbmt.2019.11.008

Nonmyeloablative haploidentical allo-bone marrow transplantation with posttransplantation cyclophosphamide is a safe and effective treatment option for patients with chronic lymphocytic leukemia (CLL), according to a study published in Biology of Blood and Marrow Transplantation.

The number of patients undergoing haploidentical allo-BMT has increased substantially, with the advent of new graft-versus-host disease (GVHD) prophylaxis strategies, such as posttransplantation cyclophosphamide (PTCy), that reduce the risk of GVHD complications; however there have been few studies assessing the results of this treatment regimen, according to the authors.

The study assessed 64 consecutive patients with CLL between Jan. 2005 and Aug. 2018 who underwent haploidentical allo-BMT. The median age was 59 years; 4 patients (6.2%) underwent allo-BMT after first-line treatment; 20 patients (31.2%) underwent allo-BMT after second-line treatment, and 40 patients (62.5%) underwent allo-BMT after three or more lines of treatment for relapsed and/or refractory disease.

All patients received a nonmyeloablative (NMA) conditioning regimen consisting of fludarabine, cyclophosphamide, and 200 cGy total body irradiation. Patients received PTCy (i.v. 50 mg/kg per day) on days +3 and +4, along with additional GVHD prophylaxis with mycophenolate mofetil between days +5 and +35 and tacrolimus or sirolimus between days +5 and +180.

For all 64 patients, the median duration of follow-up was 4.4 years based on the reverse Kaplan-Meier method. The 4-year overall survival (OS) was 52%, and the 4-year progression-free survival (PFS) was 37%. The 56 patients with less than 20% marrow CLL involvement before undergoing allo-BMT had a 4-year OS of 61%, a 4-year PFS of 43%, and a median OS of 4.8 years, according to the authors.

Regression analysis demonstrated that donor age, stem cell source, IGHV mutation status, or grade II-III acute GVHD did not affect risk of progression or survival.

“The majority of our patients had unfavorable risk factors, and collectively our data show that haploidentical allo-BMT with PTCy in CLL with less than 20% marrow involvement is a safe treatment option carrying a low risk of serious GVHD and other toxicities,” the researchers concluded.

The study was supported by National Institutes of Health, National Cancer Institute grants. The authors reported that they had no disclosures.

[email protected]

SOURCE: Suman P et al. Biol Blood Marrow Transplant. 2020 Mar 1;26:502-8. doi: 10.1016/j.bbmt.2019.11.008

A chimeric antigen receptor (CAR) construct using transduced natural killer cells instead of T cells was associated with a high complete remission rate without the cytokine release syndrome frequently seen with CAR T cell therapy, early clinical trial results show.

The construct, consisting of natural killer (NK) cells derived from umbilical cord blood that have been transduced to target CD19-expressing cells combined with interleukin 15 and equipped with an “off” switch, offers the prospect of an off-the-shelf CAR product, reported Enli Liu, MD, and colleagues at the University of Texas MD Anderson Cancer Center in Houston.

“We found that allogeneic CAR-NK cells can be delivered in adoptive transfer without the serious cytokine release syndrome and neurologic toxic effects that have been associated with CAR T-cell therapy,” they wrote in The New England Journal of Medicine.

The modified NK cells were delivered to 9 of 11 patients with only partial human leukocyte antigen (HLA) matching, and in 2 patients with no matching, yet there were no cases of graft-versus host disease (GvHD), and no patients had symptoms of cytokine release syndrome (CRS), neurotoxicity, or hemophagocytic lymphohistiocytosis.

CAR T cell production “is a cumbersome process that requires coordination and collection of the cells and there’s several weeks of manufacturing, during which time patients often can have their lymphoma worsen, and so at times it’s a little bit of a race against the clock to get those cells manufactured,” Brian Hill, MD, PhD, director of the lymphoid malignancies program at Taussig Cancer Institute at Cleveland Clinic, said in an interview.

Dr. Hill, who was not involved in the study, said that the proof-of-principle study shows promising early results and offers the prospect of an effective and safe off-the-shelf therapeutic option for patients with lymphoid malignancies.
 

Advanced B-cell cancers

The investigators conducted a phase 1/2 trial in patients with B-cell lymphoid malignancies, including five patients with chronic lymphocytic leukemia (CLL), one patient with Richter’s transformation and one with accelerated CLL, three with transformed follicular lymphoma, two with diffuse large B-cell lymphoma (DLBCL), and one with follicular lymphoma (focally grade 3B).

The patients were all heavily pretreated, with 3 to as many as 11 prior lines of therapy.

The patients received cord blood-derived NK cells that had been transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch.

The cells were expanded in the lab and after the patients underwent lymphodepleting chemotherapy, they received the cells in a single infusion at one of three doses, either 1×10⁵, 1×10⁶, or 1×10⁷ CAR-NK cells per kilogram of body weight.

As noted before, there were no cases of CRS, neurotoxicity, or GvHD and no increase over baseline in inflammatory cytokines, including interleukin-6, a key factor in the development and severity of CRS. The maximum tolerated dose was not reached.
 

Early efficacy

Of the 11 patients, 8 had a clinical response, and 7 had a complete remission, including 4 patients with lymphomas and 3 with CLL.

The patient with CLL with Richter’s transformation had a remission of the Richter’s component, but not of the CLL itself.

“This is particularly remarkable, because these patients are notoriously very difficult to treat, and the efficacy of autologous CAR T cell therapy in CLL and Richter’s patients has been hampered by lack of fitness of the patient’s own T cells when manufacturing the CAR T cell product, so this approach may obviate the need for autologous T cells in these patients,” Dr. Hill said.

The responses were rapid and occurred within 30 days of infusion at all dose levels. In addition, there was evidence of expansion and persistence of the modified NK cells at low levels for at least 1 year, despite the HLA mismatches between the NK cells and the recipients. The investigators speculated that the inclusion of interleukin-15 in the NL construct may at least partially account for the persistence of the cells and their antitumor activity.

Of the eight patients with a response, five had postremission therapy, including two patients with CLL who had minimal residual disease (MRD), one patient with follicular lymphoma and one with transformed follicular lymphoma who underwent hematopoietic stem-cell transplantation while in complete remission without evidence of MRD, and the patient with CLLL with Richter’s transformation with remission of the lymphoma component, who received a course of venetoclax.

The authors acknowledged that it may be difficult to assess the durability of response after CAR NK therapy in this study because of the allowed consolidation therapy for patients in remission.

They noted that although the patients in the current study each had a fresh CAR NK product manufactured for them, “we have shown that it is possible to produce more than 100 doses of CAR-NK cells from a single cord-blood unit. This capability, together with the apparently minimal HLA-matching requirements between the donor of CAR-NK cells and the patient, may pave the way for a truly off-the-shelf product that could increase treatment accessibility for many more patients.”

The National Institutes of Health supported the study. Dr. Liu disclosed a pending patent for methods of production of CAR-NK cells, and a patent held by MD Anderson for methods of treatment with NK cells. Dr. Hill is a member of the Hematology News editorial advisory board.

SOURCE: Liu E et al. N Engl J Med. 2020 Feb 6;382:545-53.

A chimeric antigen receptor (CAR) construct using transduced natural killer cells instead of T cells was associated with a high complete remission rate without the cytokine release syndrome frequently seen with CAR T cell therapy, early clinical trial results show.

The construct, consisting of natural killer (NK) cells derived from umbilical cord blood that have been transduced to target CD19-expressing cells combined with interleukin 15 and equipped with an “off” switch, offers the prospect of an off-the-shelf CAR product, reported Enli Liu, MD, and colleagues at the University of Texas MD Anderson Cancer Center in Houston.

“We found that allogeneic CAR-NK cells can be delivered in adoptive transfer without the serious cytokine release syndrome and neurologic toxic effects that have been associated with CAR T-cell therapy,” they wrote in The New England Journal of Medicine.

The modified NK cells were delivered to 9 of 11 patients with only partial human leukocyte antigen (HLA) matching, and in 2 patients with no matching, yet there were no cases of graft-versus host disease (GvHD), and no patients had symptoms of cytokine release syndrome (CRS), neurotoxicity, or hemophagocytic lymphohistiocytosis.

CAR T cell production “is a cumbersome process that requires coordination and collection of the cells and there’s several weeks of manufacturing, during which time patients often can have their lymphoma worsen, and so at times it’s a little bit of a race against the clock to get those cells manufactured,” Brian Hill, MD, PhD, director of the lymphoid malignancies program at Taussig Cancer Institute at Cleveland Clinic, said in an interview.

Dr. Hill, who was not involved in the study, said that the proof-of-principle study shows promising early results and offers the prospect of an effective and safe off-the-shelf therapeutic option for patients with lymphoid malignancies.
 

Advanced B-cell cancers

The investigators conducted a phase 1/2 trial in patients with B-cell lymphoid malignancies, including five patients with chronic lymphocytic leukemia (CLL), one patient with Richter’s transformation and one with accelerated CLL, three with transformed follicular lymphoma, two with diffuse large B-cell lymphoma (DLBCL), and one with follicular lymphoma (focally grade 3B).

The patients were all heavily pretreated, with 3 to as many as 11 prior lines of therapy.

The patients received cord blood-derived NK cells that had been transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch.

The cells were expanded in the lab and after the patients underwent lymphodepleting chemotherapy, they received the cells in a single infusion at one of three doses, either 1×10⁵, 1×10⁶, or 1×10⁷ CAR-NK cells per kilogram of body weight.

As noted before, there were no cases of CRS, neurotoxicity, or GvHD and no increase over baseline in inflammatory cytokines, including interleukin-6, a key factor in the development and severity of CRS. The maximum tolerated dose was not reached.
 

Early efficacy

Of the 11 patients, 8 had a clinical response, and 7 had a complete remission, including 4 patients with lymphomas and 3 with CLL.

The patient with CLL with Richter’s transformation had a remission of the Richter’s component, but not of the CLL itself.

“This is particularly remarkable, because these patients are notoriously very difficult to treat, and the efficacy of autologous CAR T cell therapy in CLL and Richter’s patients has been hampered by lack of fitness of the patient’s own T cells when manufacturing the CAR T cell product, so this approach may obviate the need for autologous T cells in these patients,” Dr. Hill said.

The responses were rapid and occurred within 30 days of infusion at all dose levels. In addition, there was evidence of expansion and persistence of the modified NK cells at low levels for at least 1 year, despite the HLA mismatches between the NK cells and the recipients. The investigators speculated that the inclusion of interleukin-15 in the NL construct may at least partially account for the persistence of the cells and their antitumor activity.

Of the eight patients with a response, five had postremission therapy, including two patients with CLL who had minimal residual disease (MRD), one patient with follicular lymphoma and one with transformed follicular lymphoma who underwent hematopoietic stem-cell transplantation while in complete remission without evidence of MRD, and the patient with CLLL with Richter’s transformation with remission of the lymphoma component, who received a course of venetoclax.

The authors acknowledged that it may be difficult to assess the durability of response after CAR NK therapy in this study because of the allowed consolidation therapy for patients in remission.

They noted that although the patients in the current study each had a fresh CAR NK product manufactured for them, “we have shown that it is possible to produce more than 100 doses of CAR-NK cells from a single cord-blood unit. This capability, together with the apparently minimal HLA-matching requirements between the donor of CAR-NK cells and the patient, may pave the way for a truly off-the-shelf product that could increase treatment accessibility for many more patients.”

The National Institutes of Health supported the study. Dr. Liu disclosed a pending patent for methods of production of CAR-NK cells, and a patent held by MD Anderson for methods of treatment with NK cells. Dr. Hill is a member of the Hematology News editorial advisory board.

SOURCE: Liu E et al. N Engl J Med. 2020 Feb 6;382:545-53.

A chimeric antigen receptor (CAR) construct using transduced natural killer cells instead of T cells was associated with a high complete remission rate without the cytokine release syndrome frequently seen with CAR T cell therapy, early clinical trial results show.

The construct, consisting of natural killer (NK) cells derived from umbilical cord blood that have been transduced to target CD19-expressing cells combined with interleukin 15 and equipped with an “off” switch, offers the prospect of an off-the-shelf CAR product, reported Enli Liu, MD, and colleagues at the University of Texas MD Anderson Cancer Center in Houston.

“We found that allogeneic CAR-NK cells can be delivered in adoptive transfer without the serious cytokine release syndrome and neurologic toxic effects that have been associated with CAR T-cell therapy,” they wrote in The New England Journal of Medicine.

The modified NK cells were delivered to 9 of 11 patients with only partial human leukocyte antigen (HLA) matching, and in 2 patients with no matching, yet there were no cases of graft-versus host disease (GvHD), and no patients had symptoms of cytokine release syndrome (CRS), neurotoxicity, or hemophagocytic lymphohistiocytosis.

CAR T cell production “is a cumbersome process that requires coordination and collection of the cells and there’s several weeks of manufacturing, during which time patients often can have their lymphoma worsen, and so at times it’s a little bit of a race against the clock to get those cells manufactured,” Brian Hill, MD, PhD, director of the lymphoid malignancies program at Taussig Cancer Institute at Cleveland Clinic, said in an interview.

Dr. Hill, who was not involved in the study, said that the proof-of-principle study shows promising early results and offers the prospect of an effective and safe off-the-shelf therapeutic option for patients with lymphoid malignancies.
 

Advanced B-cell cancers

The investigators conducted a phase 1/2 trial in patients with B-cell lymphoid malignancies, including five patients with chronic lymphocytic leukemia (CLL), one patient with Richter’s transformation and one with accelerated CLL, three with transformed follicular lymphoma, two with diffuse large B-cell lymphoma (DLBCL), and one with follicular lymphoma (focally grade 3B).

The patients were all heavily pretreated, with 3 to as many as 11 prior lines of therapy.

The patients received cord blood-derived NK cells that had been transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch.

The cells were expanded in the lab and after the patients underwent lymphodepleting chemotherapy, they received the cells in a single infusion at one of three doses, either 1×10⁵, 1×10⁶, or 1×10⁷ CAR-NK cells per kilogram of body weight.

As noted before, there were no cases of CRS, neurotoxicity, or GvHD and no increase over baseline in inflammatory cytokines, including interleukin-6, a key factor in the development and severity of CRS. The maximum tolerated dose was not reached.
 

Early efficacy

Of the 11 patients, 8 had a clinical response, and 7 had a complete remission, including 4 patients with lymphomas and 3 with CLL.

The patient with CLL with Richter’s transformation had a remission of the Richter’s component, but not of the CLL itself.

“This is particularly remarkable, because these patients are notoriously very difficult to treat, and the efficacy of autologous CAR T cell therapy in CLL and Richter’s patients has been hampered by lack of fitness of the patient’s own T cells when manufacturing the CAR T cell product, so this approach may obviate the need for autologous T cells in these patients,” Dr. Hill said.

The responses were rapid and occurred within 30 days of infusion at all dose levels. In addition, there was evidence of expansion and persistence of the modified NK cells at low levels for at least 1 year, despite the HLA mismatches between the NK cells and the recipients. The investigators speculated that the inclusion of interleukin-15 in the NL construct may at least partially account for the persistence of the cells and their antitumor activity.

Of the eight patients with a response, five had postremission therapy, including two patients with CLL who had minimal residual disease (MRD), one patient with follicular lymphoma and one with transformed follicular lymphoma who underwent hematopoietic stem-cell transplantation while in complete remission without evidence of MRD, and the patient with CLLL with Richter’s transformation with remission of the lymphoma component, who received a course of venetoclax.

The authors acknowledged that it may be difficult to assess the durability of response after CAR NK therapy in this study because of the allowed consolidation therapy for patients in remission.

They noted that although the patients in the current study each had a fresh CAR NK product manufactured for them, “we have shown that it is possible to produce more than 100 doses of CAR-NK cells from a single cord-blood unit. This capability, together with the apparently minimal HLA-matching requirements between the donor of CAR-NK cells and the patient, may pave the way for a truly off-the-shelf product that could increase treatment accessibility for many more patients.”

The National Institutes of Health supported the study. Dr. Liu disclosed a pending patent for methods of production of CAR-NK cells, and a patent held by MD Anderson for methods of treatment with NK cells. Dr. Hill is a member of the Hematology News editorial advisory board.

SOURCE: Liu E et al. N Engl J Med. 2020 Feb 6;382:545-53.

Newly discovered gene mutations in the progression of venetoclax-treated relapsed chronic lymphocytic leukemia (CLL) may improve understanding of clinical resistance mechanisms underlying the disease, according to recent research.

“We investigated patients with progressive CLL on venetoclax harboring subclonal BCL2 Gly101Val mutations for the presence of additional acquired BCL2 resistance mutations,” wrote Piers Blombery, MBBS, of the University of Melbourne in Victoria, Australia, and his colleagues in Blood.

Among 67 patients with relapsed disease treated with the BCL2 inhibitor venetoclax, the researchers identified a total of 11 patients with co-occurring BCL2 Gly101Val mutations. Each patient was enrolled in an early phase clinical trial at an institution in Australia.

With respect to testing methods, next-generation sequencing (NGS) and hybridization-based target enrichment technologies were used to detect novel acquired mutations in the BCL2 coding region.

Among those harboring the Gly101Val mutation, additional BCL2 mutations were identified in 10 patients (91%), with a median of three mutations detected per patient (range, 1-7). Previously undescribed mutations included an in-frame insertion mutation (Arg107_Arg110dup), and other substitutions (Asp103/Val156) in the BCL2 gene.

“As with the Gly101Val, these observations support the specificity of these mutations for the context of venetoclax resistance,” they wrote.

The investigators further explained that the BCL2 Asp103Glu mutation could have particular significance in the context of venetoclax sensitivity because of selective targeting of the BCL2 gene.

In comparison to wild-type aspartic acid, the BCL2 Asp103Glu substitution was linked to an approximate 20-fold reduction in affinity for venetoclax, they reported.

“[Our findings] consolidate the paradigm emerging across hematological malignancies of multiple independent molecular mechanisms underpinning an ‘oligoclonal’ pattern of clinical relapse on targeted therapies,” they concluded.

Further studies are needed to fully characterize the relationship between acquired BCL2 mutations and venetoclax resistance.

The study was funded by the Snowdome Foundation, Vision Super and the Wilson Centre for Lymphoma Genomics, the Leukemia and Lymphoma Society, the National Health and Medical Research Council of Australia, and other grant funding sources provided to the study authors. The authors reported financial affiliations with AbbVie, Genentech, and the Walter and Eliza Hall Institute.

Newly discovered gene mutations in the progression of venetoclax-treated relapsed chronic lymphocytic leukemia (CLL) may improve understanding of clinical resistance mechanisms underlying the disease, according to recent research.

“We investigated patients with progressive CLL on venetoclax harboring subclonal BCL2 Gly101Val mutations for the presence of additional acquired BCL2 resistance mutations,” wrote Piers Blombery, MBBS, of the University of Melbourne in Victoria, Australia, and his colleagues in Blood.

Among 67 patients with relapsed disease treated with the BCL2 inhibitor venetoclax, the researchers identified a total of 11 patients with co-occurring BCL2 Gly101Val mutations. Each patient was enrolled in an early phase clinical trial at an institution in Australia.

With respect to testing methods, next-generation sequencing (NGS) and hybridization-based target enrichment technologies were used to detect novel acquired mutations in the BCL2 coding region.

Among those harboring the Gly101Val mutation, additional BCL2 mutations were identified in 10 patients (91%), with a median of three mutations detected per patient (range, 1-7). Previously undescribed mutations included an in-frame insertion mutation (Arg107_Arg110dup), and other substitutions (Asp103/Val156) in the BCL2 gene.

“As with the Gly101Val, these observations support the specificity of these mutations for the context of venetoclax resistance,” they wrote.

The investigators further explained that the BCL2 Asp103Glu mutation could have particular significance in the context of venetoclax sensitivity because of selective targeting of the BCL2 gene.

In comparison to wild-type aspartic acid, the BCL2 Asp103Glu substitution was linked to an approximate 20-fold reduction in affinity for venetoclax, they reported.

“[Our findings] consolidate the paradigm emerging across hematological malignancies of multiple independent molecular mechanisms underpinning an ‘oligoclonal’ pattern of clinical relapse on targeted therapies,” they concluded.

Further studies are needed to fully characterize the relationship between acquired BCL2 mutations and venetoclax resistance.

The study was funded by the Snowdome Foundation, Vision Super and the Wilson Centre for Lymphoma Genomics, the Leukemia and Lymphoma Society, the National Health and Medical Research Council of Australia, and other grant funding sources provided to the study authors. The authors reported financial affiliations with AbbVie, Genentech, and the Walter and Eliza Hall Institute.

Newly discovered gene mutations in the progression of venetoclax-treated relapsed chronic lymphocytic leukemia (CLL) may improve understanding of clinical resistance mechanisms underlying the disease, according to recent research.

“We investigated patients with progressive CLL on venetoclax harboring subclonal BCL2 Gly101Val mutations for the presence of additional acquired BCL2 resistance mutations,” wrote Piers Blombery, MBBS, of the University of Melbourne in Victoria, Australia, and his colleagues in Blood.

Among 67 patients with relapsed disease treated with the BCL2 inhibitor venetoclax, the researchers identified a total of 11 patients with co-occurring BCL2 Gly101Val mutations. Each patient was enrolled in an early phase clinical trial at an institution in Australia.

With respect to testing methods, next-generation sequencing (NGS) and hybridization-based target enrichment technologies were used to detect novel acquired mutations in the BCL2 coding region.

Among those harboring the Gly101Val mutation, additional BCL2 mutations were identified in 10 patients (91%), with a median of three mutations detected per patient (range, 1-7). Previously undescribed mutations included an in-frame insertion mutation (Arg107_Arg110dup), and other substitutions (Asp103/Val156) in the BCL2 gene.

“As with the Gly101Val, these observations support the specificity of these mutations for the context of venetoclax resistance,” they wrote.

The investigators further explained that the BCL2 Asp103Glu mutation could have particular significance in the context of venetoclax sensitivity because of selective targeting of the BCL2 gene.

In comparison to wild-type aspartic acid, the BCL2 Asp103Glu substitution was linked to an approximate 20-fold reduction in affinity for venetoclax, they reported.

“[Our findings] consolidate the paradigm emerging across hematological malignancies of multiple independent molecular mechanisms underpinning an ‘oligoclonal’ pattern of clinical relapse on targeted therapies,” they concluded.

Further studies are needed to fully characterize the relationship between acquired BCL2 mutations and venetoclax resistance.

The study was funded by the Snowdome Foundation, Vision Super and the Wilson Centre for Lymphoma Genomics, the Leukemia and Lymphoma Society, the National Health and Medical Research Council of Australia, and other grant funding sources provided to the study authors. The authors reported financial affiliations with AbbVie, Genentech, and the Walter and Eliza Hall Institute.

For elderly patients with chronic lymphocytic leukemia (CLL) and comorbidities, the anti-CD20 monoclonal antibody ofatumumab may be a safe and effective treatment option, according to a recent phase 2 trial.

Among 32 patients with a median age of 73 years, the overall response rate was 72%, and no grade 4 adverse events occurred, reported lead author Candida Vitale, MD, PhD, of the University of Torino (Italy) and colleagues.

These findings help fill in a knowledge gap created by clinical trial exclusions, which currently make treatment planning “a significant challenge,” the investigators wrote in Journal of Geriatric Oncology.

The study, which was conducted at MD Anderson Cancer Center in Houston, enrolled 34 treatment-naive patients with CLL who were 65 years or older. All patients had an Eastern Cooperative Oncology Group performance status of 2 or 3, or a Charlson comorbidity index of at least 2. Patients with other serious medical conditions and/or primary malignancies were eligible, given that they were not already receiving anticancer therapy.

More than half of the patients (53%) had advanced-stage disease and almost one-third (29%) had at least one other primary cancer diagnosis. Many patients also had high-risk disease characteristics, including a complex karyotype involving three or more chromosomal abnormalities (15%), and/or unmutated immunoglobulin heavy chain variable region (IGHV, 59%).

Among 32 patients eligible for efficacy analysis, the overall response rate was 72%, of which 53% were partial and 19% were complete. Six percent (6%) of patients achieved minimal residual disease negativity. The benefits of ofatumumab extended to patients with high-risk disease characteristics, including unmutated IGHV (65% response rate) and/or a complex karyotype (60% response rate).

Ofatumumab also demonstrated a favorable safety profile, according to the investigators.

With all 34 patients evaluable for safety data, 19 (56%) experienced a grade 1 or 2 infusion-related reaction, and 1 (3%) experienced a grade 3 infusion-related reaction. Twenty-one grade 2 infections were reported, and one grade 3 infection occurred. Other grade 3 treatment-related adverse events included gastrointestinal disturbances, pulmonary embolism, allergic reaction, and hyperglycemia, each of which occurred in one patient. No grade 4 adverse events, or grade 2 or higher hematologic toxicities occurred.

“Our findings show that older patients with poor performance status and comorbidities can safely undergo treatment with ofatumumab,” the investigators concluded. “[The results] also support the possibility of enrolling these patients in clinical trials, so that a larger number of patients will be included and their characteristics will more closely mirror those of typical patients seen in the community.”

The study was funded by Novartis, which markets the antibody. The investigators reported additional relationships with AbbVie, Roche, Celgene, and others.

SOURCE: Vitale et al. J Geriatr Oncol. 2019 Apr 18. doi: 10.1016/j.jgo.2019.04.002.

For elderly patients with chronic lymphocytic leukemia (CLL) and comorbidities, the anti-CD20 monoclonal antibody ofatumumab may be a safe and effective treatment option, according to a recent phase 2 trial.

Among 32 patients with a median age of 73 years, the overall response rate was 72%, and no grade 4 adverse events occurred, reported lead author Candida Vitale, MD, PhD, of the University of Torino (Italy) and colleagues.

These findings help fill in a knowledge gap created by clinical trial exclusions, which currently make treatment planning “a significant challenge,” the investigators wrote in Journal of Geriatric Oncology.

The study, which was conducted at MD Anderson Cancer Center in Houston, enrolled 34 treatment-naive patients with CLL who were 65 years or older. All patients had an Eastern Cooperative Oncology Group performance status of 2 or 3, or a Charlson comorbidity index of at least 2. Patients with other serious medical conditions and/or primary malignancies were eligible, given that they were not already receiving anticancer therapy.

More than half of the patients (53%) had advanced-stage disease and almost one-third (29%) had at least one other primary cancer diagnosis. Many patients also had high-risk disease characteristics, including a complex karyotype involving three or more chromosomal abnormalities (15%), and/or unmutated immunoglobulin heavy chain variable region (IGHV, 59%).

Among 32 patients eligible for efficacy analysis, the overall response rate was 72%, of which 53% were partial and 19% were complete. Six percent (6%) of patients achieved minimal residual disease negativity. The benefits of ofatumumab extended to patients with high-risk disease characteristics, including unmutated IGHV (65% response rate) and/or a complex karyotype (60% response rate).

Ofatumumab also demonstrated a favorable safety profile, according to the investigators.

With all 34 patients evaluable for safety data, 19 (56%) experienced a grade 1 or 2 infusion-related reaction, and 1 (3%) experienced a grade 3 infusion-related reaction. Twenty-one grade 2 infections were reported, and one grade 3 infection occurred. Other grade 3 treatment-related adverse events included gastrointestinal disturbances, pulmonary embolism, allergic reaction, and hyperglycemia, each of which occurred in one patient. No grade 4 adverse events, or grade 2 or higher hematologic toxicities occurred.

“Our findings show that older patients with poor performance status and comorbidities can safely undergo treatment with ofatumumab,” the investigators concluded. “[The results] also support the possibility of enrolling these patients in clinical trials, so that a larger number of patients will be included and their characteristics will more closely mirror those of typical patients seen in the community.”

The study was funded by Novartis, which markets the antibody. The investigators reported additional relationships with AbbVie, Roche, Celgene, and others.

SOURCE: Vitale et al. J Geriatr Oncol. 2019 Apr 18. doi: 10.1016/j.jgo.2019.04.002.

For elderly patients with chronic lymphocytic leukemia (CLL) and comorbidities, the anti-CD20 monoclonal antibody ofatumumab may be a safe and effective treatment option, according to a recent phase 2 trial.

Among 32 patients with a median age of 73 years, the overall response rate was 72%, and no grade 4 adverse events occurred, reported lead author Candida Vitale, MD, PhD, of the University of Torino (Italy) and colleagues.

These findings help fill in a knowledge gap created by clinical trial exclusions, which currently make treatment planning “a significant challenge,” the investigators wrote in Journal of Geriatric Oncology.

The study, which was conducted at MD Anderson Cancer Center in Houston, enrolled 34 treatment-naive patients with CLL who were 65 years or older. All patients had an Eastern Cooperative Oncology Group performance status of 2 or 3, or a Charlson comorbidity index of at least 2. Patients with other serious medical conditions and/or primary malignancies were eligible, given that they were not already receiving anticancer therapy.

More than half of the patients (53%) had advanced-stage disease and almost one-third (29%) had at least one other primary cancer diagnosis. Many patients also had high-risk disease characteristics, including a complex karyotype involving three or more chromosomal abnormalities (15%), and/or unmutated immunoglobulin heavy chain variable region (IGHV, 59%).

Among 32 patients eligible for efficacy analysis, the overall response rate was 72%, of which 53% were partial and 19% were complete. Six percent (6%) of patients achieved minimal residual disease negativity. The benefits of ofatumumab extended to patients with high-risk disease characteristics, including unmutated IGHV (65% response rate) and/or a complex karyotype (60% response rate).

Ofatumumab also demonstrated a favorable safety profile, according to the investigators.

With all 34 patients evaluable for safety data, 19 (56%) experienced a grade 1 or 2 infusion-related reaction, and 1 (3%) experienced a grade 3 infusion-related reaction. Twenty-one grade 2 infections were reported, and one grade 3 infection occurred. Other grade 3 treatment-related adverse events included gastrointestinal disturbances, pulmonary embolism, allergic reaction, and hyperglycemia, each of which occurred in one patient. No grade 4 adverse events, or grade 2 or higher hematologic toxicities occurred.

“Our findings show that older patients with poor performance status and comorbidities can safely undergo treatment with ofatumumab,” the investigators concluded. “[The results] also support the possibility of enrolling these patients in clinical trials, so that a larger number of patients will be included and their characteristics will more closely mirror those of typical patients seen in the community.”

The study was funded by Novartis, which markets the antibody. The investigators reported additional relationships with AbbVie, Roche, Celgene, and others.

SOURCE: Vitale et al. J Geriatr Oncol. 2019 Apr 18. doi: 10.1016/j.jgo.2019.04.002.

Chimeric antigen receptor (CAR) T-cell therapy is generally associated with good long-term neuropsychiatric status, based on a recent patient-reported outcomes study.

But almost one out of five patients may have notably worse cognitive and psychiatric outcomes within 1-5 years of therapy, reported Julia Ruark, MD, of the University of Washington, Seattle, and colleagues. According to Dr. Ruark and associates, this latter finding suggests that CAR T-cell therapy may negatively impact mental health in a subset of patients.

These findings provide clinical insight into a minimally researched patient population.

“At this time, only limited data are available regarding the long-term effects of CAR T-cell therapy,” the investigators wrote in Biology of Blood and Marrow Transplantation. “Thus, it is important to evaluate the late neuropsychiatric effects of CAR T and evaluate their effect on survivors’ quality of life.”

The study involved 40 patients with relapsed or refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia. Before undergoing CAR T-cell therapy, patients underwent standardized mental health screening with validated instruments such as the 7-item Generalized Anxiety Disorder scale. At least 1 year after CAR T-cell therapy, patients completed a questionnaire consisting of the Patient-Reported Outcomes Measurement Information System (PROMIS) Scale v1.2 Global Health and the PROMIS-29 Profile v2.1, and 30 additional questions, 4 of which evaluated cognitive function. These data were converted to T scores for comparative purposes.

Patients who underwent CAR T-cell therapy had statistically similar T scores to the general population mean, suggesting comparable overall neuropsychiatric status. However, a closer look at the data showed that almost one out of five patients who underwent CAR T-cell therapy had global mental health scores that were at least 1 standard deviation lower than the mean for the general population and patients with cancer.

Almost half of the patients (47.5%) who underwent CAR T-cell therapy reported at least one clinically meaningful negative neuropsychiatric outcome. Specifically, 20% reported cognitive difficulties and depression or anxiety, 17.5% reported cognitive difficulties without depression or anxiety, and 10% reported depression or anxiety without cognitive difficulties. One-quarter (25%) of patients reported taking a medication for depression, 20% reported use of anxiolytics, and 15% reported use of sleep medications. Multivariate analysis revealed an association between younger age and depression (P = .01), anxiety (P = .001), and worse long-term global mental health (P = .02). Cognitive difficulties were significantly more common among patients with worse physical and/or mental health.

“[A] subset of patients may experience psychiatric symptoms or cognitive impairment [which may be related to CAR T-cell therapy or other treatments patients have been exposed to], and it is important to identify those patients to assist with intervention strategies,” the investigators concluded.The study was funded by the National Institutes of Health, Life Science Discovery Fund, Juno Therapeutics/Celgene, and others. The investigators reported additional relationships with Nektar Therapeutics, Allogene Therapeutics, T-CURX, and others.

SOURCE: Ruark J et al. Biol Blood Marrow Transplant. 2019 Oct 9. doi: 10.1016/j.bbmt.2019.09.037.

Chimeric antigen receptor (CAR) T-cell therapy is generally associated with good long-term neuropsychiatric status, based on a recent patient-reported outcomes study.

But almost one out of five patients may have notably worse cognitive and psychiatric outcomes within 1-5 years of therapy, reported Julia Ruark, MD, of the University of Washington, Seattle, and colleagues. According to Dr. Ruark and associates, this latter finding suggests that CAR T-cell therapy may negatively impact mental health in a subset of patients.

These findings provide clinical insight into a minimally researched patient population.

“At this time, only limited data are available regarding the long-term effects of CAR T-cell therapy,” the investigators wrote in Biology of Blood and Marrow Transplantation. “Thus, it is important to evaluate the late neuropsychiatric effects of CAR T and evaluate their effect on survivors’ quality of life.”

The study involved 40 patients with relapsed or refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia. Before undergoing CAR T-cell therapy, patients underwent standardized mental health screening with validated instruments such as the 7-item Generalized Anxiety Disorder scale. At least 1 year after CAR T-cell therapy, patients completed a questionnaire consisting of the Patient-Reported Outcomes Measurement Information System (PROMIS) Scale v1.2 Global Health and the PROMIS-29 Profile v2.1, and 30 additional questions, 4 of which evaluated cognitive function. These data were converted to T scores for comparative purposes.

Patients who underwent CAR T-cell therapy had statistically similar T scores to the general population mean, suggesting comparable overall neuropsychiatric status. However, a closer look at the data showed that almost one out of five patients who underwent CAR T-cell therapy had global mental health scores that were at least 1 standard deviation lower than the mean for the general population and patients with cancer.

Almost half of the patients (47.5%) who underwent CAR T-cell therapy reported at least one clinically meaningful negative neuropsychiatric outcome. Specifically, 20% reported cognitive difficulties and depression or anxiety, 17.5% reported cognitive difficulties without depression or anxiety, and 10% reported depression or anxiety without cognitive difficulties. One-quarter (25%) of patients reported taking a medication for depression, 20% reported use of anxiolytics, and 15% reported use of sleep medications. Multivariate analysis revealed an association between younger age and depression (P = .01), anxiety (P = .001), and worse long-term global mental health (P = .02). Cognitive difficulties were significantly more common among patients with worse physical and/or mental health.

“[A] subset of patients may experience psychiatric symptoms or cognitive impairment [which may be related to CAR T-cell therapy or other treatments patients have been exposed to], and it is important to identify those patients to assist with intervention strategies,” the investigators concluded.The study was funded by the National Institutes of Health, Life Science Discovery Fund, Juno Therapeutics/Celgene, and others. The investigators reported additional relationships with Nektar Therapeutics, Allogene Therapeutics, T-CURX, and others.

SOURCE: Ruark J et al. Biol Blood Marrow Transplant. 2019 Oct 9. doi: 10.1016/j.bbmt.2019.09.037.

Chimeric antigen receptor (CAR) T-cell therapy is generally associated with good long-term neuropsychiatric status, based on a recent patient-reported outcomes study.

But almost one out of five patients may have notably worse cognitive and psychiatric outcomes within 1-5 years of therapy, reported Julia Ruark, MD, of the University of Washington, Seattle, and colleagues. According to Dr. Ruark and associates, this latter finding suggests that CAR T-cell therapy may negatively impact mental health in a subset of patients.

These findings provide clinical insight into a minimally researched patient population.

“At this time, only limited data are available regarding the long-term effects of CAR T-cell therapy,” the investigators wrote in Biology of Blood and Marrow Transplantation. “Thus, it is important to evaluate the late neuropsychiatric effects of CAR T and evaluate their effect on survivors’ quality of life.”

The study involved 40 patients with relapsed or refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, or acute lymphoblastic leukemia. Before undergoing CAR T-cell therapy, patients underwent standardized mental health screening with validated instruments such as the 7-item Generalized Anxiety Disorder scale. At least 1 year after CAR T-cell therapy, patients completed a questionnaire consisting of the Patient-Reported Outcomes Measurement Information System (PROMIS) Scale v1.2 Global Health and the PROMIS-29 Profile v2.1, and 30 additional questions, 4 of which evaluated cognitive function. These data were converted to T scores for comparative purposes.

Patients who underwent CAR T-cell therapy had statistically similar T scores to the general population mean, suggesting comparable overall neuropsychiatric status. However, a closer look at the data showed that almost one out of five patients who underwent CAR T-cell therapy had global mental health scores that were at least 1 standard deviation lower than the mean for the general population and patients with cancer.

Almost half of the patients (47.5%) who underwent CAR T-cell therapy reported at least one clinically meaningful negative neuropsychiatric outcome. Specifically, 20% reported cognitive difficulties and depression or anxiety, 17.5% reported cognitive difficulties without depression or anxiety, and 10% reported depression or anxiety without cognitive difficulties. One-quarter (25%) of patients reported taking a medication for depression, 20% reported use of anxiolytics, and 15% reported use of sleep medications. Multivariate analysis revealed an association between younger age and depression (P = .01), anxiety (P = .001), and worse long-term global mental health (P = .02). Cognitive difficulties were significantly more common among patients with worse physical and/or mental health.

“[A] subset of patients may experience psychiatric symptoms or cognitive impairment [which may be related to CAR T-cell therapy or other treatments patients have been exposed to], and it is important to identify those patients to assist with intervention strategies,” the investigators concluded.The study was funded by the National Institutes of Health, Life Science Discovery Fund, Juno Therapeutics/Celgene, and others. The investigators reported additional relationships with Nektar Therapeutics, Allogene Therapeutics, T-CURX, and others.

SOURCE: Ruark J et al. Biol Blood Marrow Transplant. 2019 Oct 9. doi: 10.1016/j.bbmt.2019.09.037.

New data suggest an increased risk of leukemia among responders who worked at the World Trade Center site after the attacks on Sept. 11, 2001.

Courtesy Andrea Booher/FEMA News Photo

Previous studies have shown that 9/11 responders have a higher incidence of cancers than does the general population. The current study is the first to show a higher incidence of leukemia among responders. It also shows a higher incidence of thyroid and prostate cancers as well as all cancer types combined.

These findings were published in JNCI Cancer Spectrum.

“This study showed increased incidence of several cancer types compared to previously conducted studies with shorter follow-up periods,” study author Susan L, Teitelbaum, PhD, of the Icahn School of Medicine at Mount Sinai, New York, said in a press release.

“Because of the long latency period of many types of cancer, it is possible that increased rates of other cancers, as well as World Trade Center exposure health issues, may emerge after longer periods of study.”

Dr. Teitelbaum and colleagues evaluated responders enrolled in the World Trade Center Health Program General Responder Cohort from when it was established in July 2002 through the end of follow-up, which was Dec. 31, 2013, for New York residents and Dec. 31, 2012, for residents of other states.

To be eligible for the cohort, responders must have worked on the World Trade Center rescue and recovery effort a minimum of 4 hours in the first 4 days from Sept. 11, 2001, 24 hours in September 2001, or 80 hours from September through December 2001. Responders also had to complete at least one monitoring visit.

Responders’ data were linked to data from cancer registries in New York, New Jersey, Pennsylvania, and Connecticut (where most responders lived at the time of the attacks), as well as Florida and North Carolina (where responders were known to retire). The responders were linked to the registries using probabilistic matching algorithms, which made use of information such as patient name, address, social security number, sex, race, and birth date.

The researchers noted that patients who enrolled in the General Responder Cohort had their cancer certified for federally funded treatment, and this factor might result in “sicker members disproportionately self-selecting into the program.” To reduce this potential bias, the researchers conducted a restricted analysis in which counts of cancer cases and person-years of observation began 6 months after responder enrollment.

The researchers analyzed data on 28,729 responders who primarily worked in protective services (49.0%) and construction (20.8%). Responders spent a median of 52 days on the rescue and recovery effort, and 44.4% of them had some exposure to the dust cloud caused by the collapse of the towers.

In the restricted analysis, there were 1,072 cancers observed in 999 responders. Compared with the general population, responders had a significantly higher incidence of all cancers combined, with a standardized incidence ratio (SIR) of 1.09.

Responders had a significantly higher incidence of prostate cancer (SIR,1.25), thyroid cancer (SIR, 2.19), and leukemia (SIR, 1.41). The leukemia category included acute myeloid leukemia (SIR,1.58) and chronic lymphocytic leukemia (SIR, 1.08).

“Although other studies have revealed elevated SIRs for other hematologic malignancies, this is the first reported, statistically significant, elevated SIR for leukemia,” the researchers wrote. “Leukemia is known to occur after exposure to occupational carcinogens, including benzene (burning jet fuel and other sources at the [World Trade Center] site), possibly at low levels of exposure and with a latency of several years from exposure.”

A multivariate analysis showed no association between cancer incidence and the length of time responders spent on the rescue and recovery effort or the intensity of their exposure to the dust cloud or debris pile.

The analysis did show an elevated risk of all cancers combined with each 1-year increase in responder age (hazard ratio, 1.09), among male responders (HR, 1.21), and among responders who smoked at baseline (HR, 1.29).

This research was supported by the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health. The researchers disclosed no conflicts of interest.
 

[email protected]

SOURCE: Shapiro MZ et al. JNCI Cancer Spectr. 2020 Jan 14. doi: 10.1093/jncics/pkz090.

New data suggest an increased risk of leukemia among responders who worked at the World Trade Center site after the attacks on Sept. 11, 2001.

Courtesy Andrea Booher/FEMA News Photo

Previous studies have shown that 9/11 responders have a higher incidence of cancers than does the general population. The current study is the first to show a higher incidence of leukemia among responders. It also shows a higher incidence of thyroid and prostate cancers as well as all cancer types combined.

These findings were published in JNCI Cancer Spectrum.

“This study showed increased incidence of several cancer types compared to previously conducted studies with shorter follow-up periods,” study author Susan L, Teitelbaum, PhD, of the Icahn School of Medicine at Mount Sinai, New York, said in a press release.

“Because of the long latency period of many types of cancer, it is possible that increased rates of other cancers, as well as World Trade Center exposure health issues, may emerge after longer periods of study.”

Dr. Teitelbaum and colleagues evaluated responders enrolled in the World Trade Center Health Program General Responder Cohort from when it was established in July 2002 through the end of follow-up, which was Dec. 31, 2013, for New York residents and Dec. 31, 2012, for residents of other states.

To be eligible for the cohort, responders must have worked on the World Trade Center rescue and recovery effort a minimum of 4 hours in the first 4 days from Sept. 11, 2001, 24 hours in September 2001, or 80 hours from September through December 2001. Responders also had to complete at least one monitoring visit.

Responders’ data were linked to data from cancer registries in New York, New Jersey, Pennsylvania, and Connecticut (where most responders lived at the time of the attacks), as well as Florida and North Carolina (where responders were known to retire). The responders were linked to the registries using probabilistic matching algorithms, which made use of information such as patient name, address, social security number, sex, race, and birth date.

The researchers noted that patients who enrolled in the General Responder Cohort had their cancer certified for federally funded treatment, and this factor might result in “sicker members disproportionately self-selecting into the program.” To reduce this potential bias, the researchers conducted a restricted analysis in which counts of cancer cases and person-years of observation began 6 months after responder enrollment.

The researchers analyzed data on 28,729 responders who primarily worked in protective services (49.0%) and construction (20.8%). Responders spent a median of 52 days on the rescue and recovery effort, and 44.4% of them had some exposure to the dust cloud caused by the collapse of the towers.

In the restricted analysis, there were 1,072 cancers observed in 999 responders. Compared with the general population, responders had a significantly higher incidence of all cancers combined, with a standardized incidence ratio (SIR) of 1.09.

Responders had a significantly higher incidence of prostate cancer (SIR,1.25), thyroid cancer (SIR, 2.19), and leukemia (SIR, 1.41). The leukemia category included acute myeloid leukemia (SIR,1.58) and chronic lymphocytic leukemia (SIR, 1.08).

“Although other studies have revealed elevated SIRs for other hematologic malignancies, this is the first reported, statistically significant, elevated SIR for leukemia,” the researchers wrote. “Leukemia is known to occur after exposure to occupational carcinogens, including benzene (burning jet fuel and other sources at the [World Trade Center] site), possibly at low levels of exposure and with a latency of several years from exposure.”

A multivariate analysis showed no association between cancer incidence and the length of time responders spent on the rescue and recovery effort or the intensity of their exposure to the dust cloud or debris pile.

The analysis did show an elevated risk of all cancers combined with each 1-year increase in responder age (hazard ratio, 1.09), among male responders (HR, 1.21), and among responders who smoked at baseline (HR, 1.29).

This research was supported by the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health. The researchers disclosed no conflicts of interest.
 

[email protected]

SOURCE: Shapiro MZ et al. JNCI Cancer Spectr. 2020 Jan 14. doi: 10.1093/jncics/pkz090.

New data suggest an increased risk of leukemia among responders who worked at the World Trade Center site after the attacks on Sept. 11, 2001.

Courtesy Andrea Booher/FEMA News Photo

Previous studies have shown that 9/11 responders have a higher incidence of cancers than does the general population. The current study is the first to show a higher incidence of leukemia among responders. It also shows a higher incidence of thyroid and prostate cancers as well as all cancer types combined.

These findings were published in JNCI Cancer Spectrum.

“This study showed increased incidence of several cancer types compared to previously conducted studies with shorter follow-up periods,” study author Susan L, Teitelbaum, PhD, of the Icahn School of Medicine at Mount Sinai, New York, said in a press release.

“Because of the long latency period of many types of cancer, it is possible that increased rates of other cancers, as well as World Trade Center exposure health issues, may emerge after longer periods of study.”

Dr. Teitelbaum and colleagues evaluated responders enrolled in the World Trade Center Health Program General Responder Cohort from when it was established in July 2002 through the end of follow-up, which was Dec. 31, 2013, for New York residents and Dec. 31, 2012, for residents of other states.

To be eligible for the cohort, responders must have worked on the World Trade Center rescue and recovery effort a minimum of 4 hours in the first 4 days from Sept. 11, 2001, 24 hours in September 2001, or 80 hours from September through December 2001. Responders also had to complete at least one monitoring visit.

Responders’ data were linked to data from cancer registries in New York, New Jersey, Pennsylvania, and Connecticut (where most responders lived at the time of the attacks), as well as Florida and North Carolina (where responders were known to retire). The responders were linked to the registries using probabilistic matching algorithms, which made use of information such as patient name, address, social security number, sex, race, and birth date.

The researchers noted that patients who enrolled in the General Responder Cohort had their cancer certified for federally funded treatment, and this factor might result in “sicker members disproportionately self-selecting into the program.” To reduce this potential bias, the researchers conducted a restricted analysis in which counts of cancer cases and person-years of observation began 6 months after responder enrollment.

The researchers analyzed data on 28,729 responders who primarily worked in protective services (49.0%) and construction (20.8%). Responders spent a median of 52 days on the rescue and recovery effort, and 44.4% of them had some exposure to the dust cloud caused by the collapse of the towers.

In the restricted analysis, there were 1,072 cancers observed in 999 responders. Compared with the general population, responders had a significantly higher incidence of all cancers combined, with a standardized incidence ratio (SIR) of 1.09.

Responders had a significantly higher incidence of prostate cancer (SIR,1.25), thyroid cancer (SIR, 2.19), and leukemia (SIR, 1.41). The leukemia category included acute myeloid leukemia (SIR,1.58) and chronic lymphocytic leukemia (SIR, 1.08).

“Although other studies have revealed elevated SIRs for other hematologic malignancies, this is the first reported, statistically significant, elevated SIR for leukemia,” the researchers wrote. “Leukemia is known to occur after exposure to occupational carcinogens, including benzene (burning jet fuel and other sources at the [World Trade Center] site), possibly at low levels of exposure and with a latency of several years from exposure.”

A multivariate analysis showed no association between cancer incidence and the length of time responders spent on the rescue and recovery effort or the intensity of their exposure to the dust cloud or debris pile.

The analysis did show an elevated risk of all cancers combined with each 1-year increase in responder age (hazard ratio, 1.09), among male responders (HR, 1.21), and among responders who smoked at baseline (HR, 1.29).

This research was supported by the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health. The researchers disclosed no conflicts of interest.
 

[email protected]

SOURCE: Shapiro MZ et al. JNCI Cancer Spectr. 2020 Jan 14. doi: 10.1093/jncics/pkz090.

ORLANDO – Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has demonstrated manageable toxicity and promising clinical activity in the phase 1 portion of a trial enrolling heavily pretreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, according to an investigator.

Andrew D. Bowser/MDedge News

The overall response rate exceeded 80%, and most patients in response at 6 months had maintained that response at the 9-month mark, said Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif.

“Clinical responses were rapid, improved with time, and were deep and durable,” Dr. Siddiqi said at the annual meeting of the American Society of Hematology.

These findings have provided justification for conducting the phase 2 portion of the study, which is currently enrolling at the higher of two dose levels evaluated in phase 1, she added.

Dr. Siddiqi reported on a total of 23 patients enrolled in the study, known as TRANSCEND CLL 004. All patients had relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and had received at least two prior therapies, including ibrutinib, while about one-third had failed venetoclax as well.

The median patient age was 66 years, and 83% had high-risk features, according to Dr. Siddiqi, who said patients had received a median of five prior lines of therapy.

Nine patients were treated at dose level 1, or 50 x 10⁶ CAR+ T cells, while 14 were treated at dose level 2, or 100 x 10⁶ CAR+ T cells. Two patients experienced grade 3 or 4 dose-limiting toxicities at the second level, including hypertension in one patient, and encephalopathy, muscle weakness, and tumor lysis syndrome (TLS) in the other.

Cytokine release syndrome (CRS) occurred in 17 patients, though only two cases reached grade 3. Neurologic adverse events were seen in nine patients, of which five were grade 3 or 4.

SOURCE: Siddiqi T et al. ASH 2019, Abstract 503.

ORLANDO – Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has demonstrated manageable toxicity and promising clinical activity in the phase 1 portion of a trial enrolling heavily pretreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, according to an investigator.

Andrew D. Bowser/MDedge News

The overall response rate exceeded 80%, and most patients in response at 6 months had maintained that response at the 9-month mark, said Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif.

“Clinical responses were rapid, improved with time, and were deep and durable,” Dr. Siddiqi said at the annual meeting of the American Society of Hematology.

These findings have provided justification for conducting the phase 2 portion of the study, which is currently enrolling at the higher of two dose levels evaluated in phase 1, she added.

Dr. Siddiqi reported on a total of 23 patients enrolled in the study, known as TRANSCEND CLL 004. All patients had relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and had received at least two prior therapies, including ibrutinib, while about one-third had failed venetoclax as well.

The median patient age was 66 years, and 83% had high-risk features, according to Dr. Siddiqi, who said patients had received a median of five prior lines of therapy.

Nine patients were treated at dose level 1, or 50 x 10⁶ CAR+ T cells, while 14 were treated at dose level 2, or 100 x 10⁶ CAR+ T cells. Two patients experienced grade 3 or 4 dose-limiting toxicities at the second level, including hypertension in one patient, and encephalopathy, muscle weakness, and tumor lysis syndrome (TLS) in the other.

Cytokine release syndrome (CRS) occurred in 17 patients, though only two cases reached grade 3. Neurologic adverse events were seen in nine patients, of which five were grade 3 or 4.

SOURCE: Siddiqi T et al. ASH 2019, Abstract 503.

ORLANDO – Lisocabtagene maraleucel (liso-cel), a CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has demonstrated manageable toxicity and promising clinical activity in the phase 1 portion of a trial enrolling heavily pretreated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, according to an investigator.

Andrew D. Bowser/MDedge News

The overall response rate exceeded 80%, and most patients in response at 6 months had maintained that response at the 9-month mark, said Tanya Siddiqi, MD, of City of Hope National Medical Center, Duarte, Calif.

“Clinical responses were rapid, improved with time, and were deep and durable,” Dr. Siddiqi said at the annual meeting of the American Society of Hematology.

These findings have provided justification for conducting the phase 2 portion of the study, which is currently enrolling at the higher of two dose levels evaluated in phase 1, she added.

Dr. Siddiqi reported on a total of 23 patients enrolled in the study, known as TRANSCEND CLL 004. All patients had relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and had received at least two prior therapies, including ibrutinib, while about one-third had failed venetoclax as well.

The median patient age was 66 years, and 83% had high-risk features, according to Dr. Siddiqi, who said patients had received a median of five prior lines of therapy.

Nine patients were treated at dose level 1, or 50 x 10⁶ CAR+ T cells, while 14 were treated at dose level 2, or 100 x 10⁶ CAR+ T cells. Two patients experienced grade 3 or 4 dose-limiting toxicities at the second level, including hypertension in one patient, and encephalopathy, muscle weakness, and tumor lysis syndrome (TLS) in the other.

Cytokine release syndrome (CRS) occurred in 17 patients, though only two cases reached grade 3. Neurologic adverse events were seen in nine patients, of which five were grade 3 or 4.

SOURCE: Siddiqi T et al. ASH 2019, Abstract 503.

ORLANDO – A phase 1 trial of the next-generation Bruton tyrosine kinase (BTK) inhibitor LOXO-305 has demonstrated safety and provided evidence of its efficacy in heavily pretreated patients with B-cell malignancies, including some with acquired resistance to other BTK inhibitors and venetoclax, according to an investigator.

Andrew D. Bowser/MDedge News

The antitumor activity of this highly selective investigational oral BTK inhibitor was significant in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with a rapid onset of action and resolution of lymphocytosis “consistent with effective BTK target inhibition,” said Anthony R. Mato, MD, of the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.

Responses were also seen in patients with BTK C481 mutations, the primary cause of progressive CLL after BTK inhibitor use, Dr. Mato said at the annual meeting of the American Society of Hematology.

The safety and tolerability profile of LOXO-305 is “consistent with highly selective drug design,” with no evidence of off-target effects, he said. “Collectively, these data demonstrate that BTK remains a highly actionable target despite progression on covalent BTK inhibitors.”

While BTK inhibitors have transformed treatment of B-cell malignancies, resistance remains a major problem, said Dr. Mato, citing 5-year ibrutinib discontinuation rates of 41% in the front line setting and 53.7% in the relapsed/refractory setting.

Key reasons for discontinuation are intolerance, events such as atrial fibrillation and major bleeding, progression of disease, and the appearance of BTK C481 mutations, which prevent covalent BTK inhibitors from achieving effective target inhibition, he said. In contrast, LOXO-305 is designed to non-covalently bind to BTK, regardless of C481 status.

Dr. Mato described results of the phase 1 BRUIN trial, in which 28 adult patients with CLL or B-cell non-Hodgkin lymphomas received once daily oral LOXO-305 at doses ranging from 25 mg to 200 mg. All patients had received at least two lines of prior therapy and had active disease in need of treatment.

For 13 evaluable CLL patients, the overall response rate was 77% (10 patients), Dr. Mato reported. Overall response rates for MCL and other B-cell malignancies were 50%, or three out of six MCL patients and two of four patients with Waldenström macroglobulinemia, diffuse large B-cell lymphoma, or marginal zone lymphoma.

Though only a small subset of CLL patients have had multiple response assessments, the available data suggest that responses “deepen over time” with continued LOXO-305 treatment, Dr. Mato said.

With the median follow-up of 2.7 months, 24 of 28 patients remain on therapy, including all responders. “Some of the responses appear to be quite durable,” Dr. Mato said.

There have been no dose-limiting toxicities, the maximum tolerated dose has not been reached, and there have been no notable adverse events characteristic of covalent BTK inhibitors – namely atrial fibrillation or major bleeding – despite frequent monitoring, according to Dr. Mato.

There were two grade 3 events (leukocytosis and neutropenia), but the remaining treatment-emergent adverse events have been grade 1-2. “Having managed many of these patients, I can tell you that these adverse events were quite manageable,” Dr. Mato told attendees.

BRUIN is a global trial that continues to enroll patients at 18 sites in 3 countries, with a plan in 2020 to incorporate “rational combinations” of agents, according to the investigator.

Dr. Mato reported disclosures related to Gilead, Pharmacyclics, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, LOXO, DTRM Biopharma, Genentech, Janssen, Acerta, Pharmacyclics, and Celgene.

SOURCE: Mato AR et al. ASH 2019, Abstract 501.

ORLANDO – A phase 1 trial of the next-generation Bruton tyrosine kinase (BTK) inhibitor LOXO-305 has demonstrated safety and provided evidence of its efficacy in heavily pretreated patients with B-cell malignancies, including some with acquired resistance to other BTK inhibitors and venetoclax, according to an investigator.

Andrew D. Bowser/MDedge News

The antitumor activity of this highly selective investigational oral BTK inhibitor was significant in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with a rapid onset of action and resolution of lymphocytosis “consistent with effective BTK target inhibition,” said Anthony R. Mato, MD, of the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.

Responses were also seen in patients with BTK C481 mutations, the primary cause of progressive CLL after BTK inhibitor use, Dr. Mato said at the annual meeting of the American Society of Hematology.

The safety and tolerability profile of LOXO-305 is “consistent with highly selective drug design,” with no evidence of off-target effects, he said. “Collectively, these data demonstrate that BTK remains a highly actionable target despite progression on covalent BTK inhibitors.”

While BTK inhibitors have transformed treatment of B-cell malignancies, resistance remains a major problem, said Dr. Mato, citing 5-year ibrutinib discontinuation rates of 41% in the front line setting and 53.7% in the relapsed/refractory setting.

Key reasons for discontinuation are intolerance, events such as atrial fibrillation and major bleeding, progression of disease, and the appearance of BTK C481 mutations, which prevent covalent BTK inhibitors from achieving effective target inhibition, he said. In contrast, LOXO-305 is designed to non-covalently bind to BTK, regardless of C481 status.

Dr. Mato described results of the phase 1 BRUIN trial, in which 28 adult patients with CLL or B-cell non-Hodgkin lymphomas received once daily oral LOXO-305 at doses ranging from 25 mg to 200 mg. All patients had received at least two lines of prior therapy and had active disease in need of treatment.

For 13 evaluable CLL patients, the overall response rate was 77% (10 patients), Dr. Mato reported. Overall response rates for MCL and other B-cell malignancies were 50%, or three out of six MCL patients and two of four patients with Waldenström macroglobulinemia, diffuse large B-cell lymphoma, or marginal zone lymphoma.

Though only a small subset of CLL patients have had multiple response assessments, the available data suggest that responses “deepen over time” with continued LOXO-305 treatment, Dr. Mato said.

With the median follow-up of 2.7 months, 24 of 28 patients remain on therapy, including all responders. “Some of the responses appear to be quite durable,” Dr. Mato said.

There have been no dose-limiting toxicities, the maximum tolerated dose has not been reached, and there have been no notable adverse events characteristic of covalent BTK inhibitors – namely atrial fibrillation or major bleeding – despite frequent monitoring, according to Dr. Mato.

There were two grade 3 events (leukocytosis and neutropenia), but the remaining treatment-emergent adverse events have been grade 1-2. “Having managed many of these patients, I can tell you that these adverse events were quite manageable,” Dr. Mato told attendees.

BRUIN is a global trial that continues to enroll patients at 18 sites in 3 countries, with a plan in 2020 to incorporate “rational combinations” of agents, according to the investigator.

Dr. Mato reported disclosures related to Gilead, Pharmacyclics, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, LOXO, DTRM Biopharma, Genentech, Janssen, Acerta, Pharmacyclics, and Celgene.

SOURCE: Mato AR et al. ASH 2019, Abstract 501.

ORLANDO – A phase 1 trial of the next-generation Bruton tyrosine kinase (BTK) inhibitor LOXO-305 has demonstrated safety and provided evidence of its efficacy in heavily pretreated patients with B-cell malignancies, including some with acquired resistance to other BTK inhibitors and venetoclax, according to an investigator.

Andrew D. Bowser/MDedge News

The antitumor activity of this highly selective investigational oral BTK inhibitor was significant in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with a rapid onset of action and resolution of lymphocytosis “consistent with effective BTK target inhibition,” said Anthony R. Mato, MD, of the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.

Responses were also seen in patients with BTK C481 mutations, the primary cause of progressive CLL after BTK inhibitor use, Dr. Mato said at the annual meeting of the American Society of Hematology.

The safety and tolerability profile of LOXO-305 is “consistent with highly selective drug design,” with no evidence of off-target effects, he said. “Collectively, these data demonstrate that BTK remains a highly actionable target despite progression on covalent BTK inhibitors.”

While BTK inhibitors have transformed treatment of B-cell malignancies, resistance remains a major problem, said Dr. Mato, citing 5-year ibrutinib discontinuation rates of 41% in the front line setting and 53.7% in the relapsed/refractory setting.

Key reasons for discontinuation are intolerance, events such as atrial fibrillation and major bleeding, progression of disease, and the appearance of BTK C481 mutations, which prevent covalent BTK inhibitors from achieving effective target inhibition, he said. In contrast, LOXO-305 is designed to non-covalently bind to BTK, regardless of C481 status.

Dr. Mato described results of the phase 1 BRUIN trial, in which 28 adult patients with CLL or B-cell non-Hodgkin lymphomas received once daily oral LOXO-305 at doses ranging from 25 mg to 200 mg. All patients had received at least two lines of prior therapy and had active disease in need of treatment.

For 13 evaluable CLL patients, the overall response rate was 77% (10 patients), Dr. Mato reported. Overall response rates for MCL and other B-cell malignancies were 50%, or three out of six MCL patients and two of four patients with Waldenström macroglobulinemia, diffuse large B-cell lymphoma, or marginal zone lymphoma.

Though only a small subset of CLL patients have had multiple response assessments, the available data suggest that responses “deepen over time” with continued LOXO-305 treatment, Dr. Mato said.

With the median follow-up of 2.7 months, 24 of 28 patients remain on therapy, including all responders. “Some of the responses appear to be quite durable,” Dr. Mato said.

There have been no dose-limiting toxicities, the maximum tolerated dose has not been reached, and there have been no notable adverse events characteristic of covalent BTK inhibitors – namely atrial fibrillation or major bleeding – despite frequent monitoring, according to Dr. Mato.

There were two grade 3 events (leukocytosis and neutropenia), but the remaining treatment-emergent adverse events have been grade 1-2. “Having managed many of these patients, I can tell you that these adverse events were quite manageable,” Dr. Mato told attendees.

BRUIN is a global trial that continues to enroll patients at 18 sites in 3 countries, with a plan in 2020 to incorporate “rational combinations” of agents, according to the investigator.

Dr. Mato reported disclosures related to Gilead, Pharmacyclics, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, LOXO, DTRM Biopharma, Genentech, Janssen, Acerta, Pharmacyclics, and Celgene.

SOURCE: Mato AR et al. ASH 2019, Abstract 501.

ORLANDO – Zanubrutinib has produced a high overall response rate in one the largest cohorts of patients with treatment-naive 17p-deletion chronic lymphocytic leukemia (CLL) studied to date.

Andrew D. Bowser/MDedge News

An overall response rate of nearly 93% was seen in this 109-patient, high-risk cohort, enrolled as part of the phase 3 SEQUOIA study (BGB-3111-304), said Constantine S. Tam, MBBS, MD, of St. Vincent’s Hospital and Peter MacCallum Cancer Centre in Melbourne.

Tolerability of zanubrutinib was essentially consistent with previous reports of the agent as used in other B-cell malignancies, Dr. Tam said in an oral presentation of the results at the annual meeting of the American Society of Hematology.

Deletion of chromosome 17p13.1, or del(17p), is a marker of poor prognosis and poor response to chemotherapy in patients with CLL or small lymphocytic lymphoma (SLL). For patients with del(17p) CLL, the first-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib has become a standard of care, Dr. Tam said.

Zanubrutinib, a next-generation BTK inhibitor, was developed to improve BTK occupancy and minimize off-target inhibition of TEC and epidermal growth factor receptor kinases. “What this effectively means is that we are able to dose this drug at levels much higher than that achievable with ibrutinib, and not get intolerable side effects,” Dr. Tam said.

Zanubrutinib has been approved in the United States for previously treated mantle cell lymphoma, and generated durable responses among CLL/SLL patients with or without del(17p) in a phase 1/2 study, according to Dr. Tam.

In the present study, which exclusively enrolled patients with del(17p) CLL/SLL, patients received 160 mg twice daily of zanubrutinib, Dr. Tam said. Out of 109 patients enrolled, 10 (9.2%) had SLL. All patients were aged at least 65 years or were deemed unsuitable for treatment with the combination of fludarabine, cyclophosphamide, and rituximab.

Of 109 patients enrolled, 104 received on-study treatment. The median age was 70 years, Dr. Tam reported, and a number of patients had other high-risk markers beyond del(17p), including unmutated IgVH status in 61.5% of patients.

With a median follow-up of 10 months, the overall response rate was 92.7%, including 1.9% complete responses and 78.9% partial responses. “Only one patient had primary progressive disease after starting this drug,” Dr. Tam said.

Time to response was rapid, according to the investigator, at about 2.8 months; after 6 months, 95% of responders remained in response.

Further analysis showed that the response rate was consistent across subgroups. “There was not a single group that did not respond with a high response rate, including poor prognostic groups,” Dr. Tam said.

Most adverse events were grade 1-2 in severity, and the most common events included confusion and upper respiratory tract infection. The only common grade 3 event, according to Dr. Tam, was neutropenia. Rates of grade 3 major bleeding were low, he said, and the rate of grade 3 atrial fibrillation was 0.9%. One patient died due to pneumonia.

The ongoing SEQUOIA study, designed to compare zanubrutinib to the combination of bendamustine and rituximab in patients with previously untreated CLL or SLL, is sponsored by BeiGene. Dr. Tam reported disclosures related to Novartis, Pharmacyclics, AbbVie, BeiGene, Janssen, and Roche.

SOURCE: Tam C et al. ASH 2019, Abstract 499.

ORLANDO – Zanubrutinib has produced a high overall response rate in one the largest cohorts of patients with treatment-naive 17p-deletion chronic lymphocytic leukemia (CLL) studied to date.

Andrew D. Bowser/MDedge News

An overall response rate of nearly 93% was seen in this 109-patient, high-risk cohort, enrolled as part of the phase 3 SEQUOIA study (BGB-3111-304), said Constantine S. Tam, MBBS, MD, of St. Vincent’s Hospital and Peter MacCallum Cancer Centre in Melbourne.

Tolerability of zanubrutinib was essentially consistent with previous reports of the agent as used in other B-cell malignancies, Dr. Tam said in an oral presentation of the results at the annual meeting of the American Society of Hematology.

Deletion of chromosome 17p13.1, or del(17p), is a marker of poor prognosis and poor response to chemotherapy in patients with CLL or small lymphocytic lymphoma (SLL). For patients with del(17p) CLL, the first-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib has become a standard of care, Dr. Tam said.

Zanubrutinib, a next-generation BTK inhibitor, was developed to improve BTK occupancy and minimize off-target inhibition of TEC and epidermal growth factor receptor kinases. “What this effectively means is that we are able to dose this drug at levels much higher than that achievable with ibrutinib, and not get intolerable side effects,” Dr. Tam said.

Zanubrutinib has been approved in the United States for previously treated mantle cell lymphoma, and generated durable responses among CLL/SLL patients with or without del(17p) in a phase 1/2 study, according to Dr. Tam.

In the present study, which exclusively enrolled patients with del(17p) CLL/SLL, patients received 160 mg twice daily of zanubrutinib, Dr. Tam said. Out of 109 patients enrolled, 10 (9.2%) had SLL. All patients were aged at least 65 years or were deemed unsuitable for treatment with the combination of fludarabine, cyclophosphamide, and rituximab.

Of 109 patients enrolled, 104 received on-study treatment. The median age was 70 years, Dr. Tam reported, and a number of patients had other high-risk markers beyond del(17p), including unmutated IgVH status in 61.5% of patients.

With a median follow-up of 10 months, the overall response rate was 92.7%, including 1.9% complete responses and 78.9% partial responses. “Only one patient had primary progressive disease after starting this drug,” Dr. Tam said.

Time to response was rapid, according to the investigator, at about 2.8 months; after 6 months, 95% of responders remained in response.

Further analysis showed that the response rate was consistent across subgroups. “There was not a single group that did not respond with a high response rate, including poor prognostic groups,” Dr. Tam said.

Most adverse events were grade 1-2 in severity, and the most common events included confusion and upper respiratory tract infection. The only common grade 3 event, according to Dr. Tam, was neutropenia. Rates of grade 3 major bleeding were low, he said, and the rate of grade 3 atrial fibrillation was 0.9%. One patient died due to pneumonia.

The ongoing SEQUOIA study, designed to compare zanubrutinib to the combination of bendamustine and rituximab in patients with previously untreated CLL or SLL, is sponsored by BeiGene. Dr. Tam reported disclosures related to Novartis, Pharmacyclics, AbbVie, BeiGene, Janssen, and Roche.

SOURCE: Tam C et al. ASH 2019, Abstract 499.

ORLANDO – Zanubrutinib has produced a high overall response rate in one the largest cohorts of patients with treatment-naive 17p-deletion chronic lymphocytic leukemia (CLL) studied to date.

Andrew D. Bowser/MDedge News

An overall response rate of nearly 93% was seen in this 109-patient, high-risk cohort, enrolled as part of the phase 3 SEQUOIA study (BGB-3111-304), said Constantine S. Tam, MBBS, MD, of St. Vincent’s Hospital and Peter MacCallum Cancer Centre in Melbourne.

Tolerability of zanubrutinib was essentially consistent with previous reports of the agent as used in other B-cell malignancies, Dr. Tam said in an oral presentation of the results at the annual meeting of the American Society of Hematology.

Deletion of chromosome 17p13.1, or del(17p), is a marker of poor prognosis and poor response to chemotherapy in patients with CLL or small lymphocytic lymphoma (SLL). For patients with del(17p) CLL, the first-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib has become a standard of care, Dr. Tam said.

Zanubrutinib, a next-generation BTK inhibitor, was developed to improve BTK occupancy and minimize off-target inhibition of TEC and epidermal growth factor receptor kinases. “What this effectively means is that we are able to dose this drug at levels much higher than that achievable with ibrutinib, and not get intolerable side effects,” Dr. Tam said.

Zanubrutinib has been approved in the United States for previously treated mantle cell lymphoma, and generated durable responses among CLL/SLL patients with or without del(17p) in a phase 1/2 study, according to Dr. Tam.

In the present study, which exclusively enrolled patients with del(17p) CLL/SLL, patients received 160 mg twice daily of zanubrutinib, Dr. Tam said. Out of 109 patients enrolled, 10 (9.2%) had SLL. All patients were aged at least 65 years or were deemed unsuitable for treatment with the combination of fludarabine, cyclophosphamide, and rituximab.

Of 109 patients enrolled, 104 received on-study treatment. The median age was 70 years, Dr. Tam reported, and a number of patients had other high-risk markers beyond del(17p), including unmutated IgVH status in 61.5% of patients.

With a median follow-up of 10 months, the overall response rate was 92.7%, including 1.9% complete responses and 78.9% partial responses. “Only one patient had primary progressive disease after starting this drug,” Dr. Tam said.

Time to response was rapid, according to the investigator, at about 2.8 months; after 6 months, 95% of responders remained in response.

Further analysis showed that the response rate was consistent across subgroups. “There was not a single group that did not respond with a high response rate, including poor prognostic groups,” Dr. Tam said.

Most adverse events were grade 1-2 in severity, and the most common events included confusion and upper respiratory tract infection. The only common grade 3 event, according to Dr. Tam, was neutropenia. Rates of grade 3 major bleeding were low, he said, and the rate of grade 3 atrial fibrillation was 0.9%. One patient died due to pneumonia.

The ongoing SEQUOIA study, designed to compare zanubrutinib to the combination of bendamustine and rituximab in patients with previously untreated CLL or SLL, is sponsored by BeiGene. Dr. Tam reported disclosures related to Novartis, Pharmacyclics, AbbVie, BeiGene, Janssen, and Roche.

SOURCE: Tam C et al. ASH 2019, Abstract 499.

ORLANDO – For a patient with chronic lymphocytic leukemia (CLL) who has discontinued venetoclax, choosing the best next therapy may depend on what novel agents the patient was exposed to and why they discontinued them, according to Anthony R. Mato, MD, with the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.

Andrew D. Bowser/MDedge News

If the patient is Bruton tyrosine kinase (BTK) inhibitor naive, then use of a BTK inhibitor after venetoclax would be supported, Dr. Mato said, by the high overall response rates and durable remissions that he and his coinvestigators documented in a retrospective, multicenter study designed specifically to address the gap in knowledge regarding what to use after venetoclax.

If the patient is BTK inhibitor exposed, then the reason for discontinuation needs to be considered before going with that venetoclax-to-BTK inhibitor sequence, Dr. Mato said during an oral presentation at the annual meeting of the American Society of Hematology.

“In patients with resistance to a BTK inhibitor, the sequence was not supported – it did not appear to be effective,” he said. “However, in the setting of intolerance, an alternate BTK inhibitor could be considered.”

The study did not support a venetoclax-to-PI3K inhibitor sequence in PI3K-naive patients, he added, noting that remissions did not appear to be durable, suggesting a potential overlap in resistance mechanisms between agents.

All told, the most effective therapies for in the postvenetoclax setting included the use of a BTK inhibitor in BTK inhibitor–naive or previously responsive patients, and allogeneic transplant following double novel-agent exposure.

“These data may provide support for venetoclax’s earlier use in the course of CLL, and may guide clinical practice and aid in the design of future clinical trials to address sequencing of novel agents,” Dr. Mato told attendees.

While prospective and real-world data clearly show that venetoclax is active in ibrutinib- or idelalisib-exposed patients, data are conversely “variable and limited” with regard to outcomes for next therapies following venetoclax.

“Current data addressing this key sequencing question, I feel, is a major limitation in supporting the sequence of venetoclax to a BTK inhibitor,” Dr. Mato said.

Accordingly, Dr. Mato and colleagues at 31 centers internationally planned and conducted this study, which included data on 326 patients treated with venetoclax who then discontinued for any reason.

“I wanted to highlight that 50% of the sites for this trial were recruited by a single tweet,” said Dr. Mato, adding that he and his coauthors received no funding to conduct this study and volunteered their time to complete it.

They found that, in BTK inhibitor–naive patients who discontinued venetoclax, subsequent BTK inhibitor treatment was associated with a high overall response rate and durable remissions, with a median progression-free survival (PFS) of 32 months.

In BTK inhibitor–exposed patients, response to postvenetoclax BTK inhibitor treatment depended on the reason for discontinuation, with a favorable result (PFS not reached with a mean follow-up of 7.7 months) in patients who were intolerant of the prior BTK inhibitor. By contrast, median PFS was only about 4 months for patients who were resistant to the prior BTK inhibitor.

PI3K inhibitors did not produce durable remissions after venetoclax, with a median PFS also of just 4 months, Dr. Mato reported.

However, cellular therapies appeared to be effective after venetoclax. Allogeneic hematopoietic stem cell transplantation was particularly effective, with the median PFS not reached, while chimeric antigen receptor T-cell therapy produced a PFS of 9 months.

Dr. Mato emphasized that the results of the retrospective trial were “hypothesis generating” and noted that patients in the study had received a median of 3, and up to 11, prior therapies. “This population are probably not our patients receiving venetoclax in clinical practice. They’re more heavily pretreated.”

Dr. Mato reported disclosures related to Gilead, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, Loxo Oncology, DTRM Biopharma, Genentech, Janssen, Acerta Pharma, Pharmacyclics, and Celgene.

SOURCE: Mato AR et al. ASH 2019, Abstract 502.

ORLANDO – For a patient with chronic lymphocytic leukemia (CLL) who has discontinued venetoclax, choosing the best next therapy may depend on what novel agents the patient was exposed to and why they discontinued them, according to Anthony R. Mato, MD, with the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.

Andrew D. Bowser/MDedge News

If the patient is Bruton tyrosine kinase (BTK) inhibitor naive, then use of a BTK inhibitor after venetoclax would be supported, Dr. Mato said, by the high overall response rates and durable remissions that he and his coinvestigators documented in a retrospective, multicenter study designed specifically to address the gap in knowledge regarding what to use after venetoclax.

If the patient is BTK inhibitor exposed, then the reason for discontinuation needs to be considered before going with that venetoclax-to-BTK inhibitor sequence, Dr. Mato said during an oral presentation at the annual meeting of the American Society of Hematology.

“In patients with resistance to a BTK inhibitor, the sequence was not supported – it did not appear to be effective,” he said. “However, in the setting of intolerance, an alternate BTK inhibitor could be considered.”

The study did not support a venetoclax-to-PI3K inhibitor sequence in PI3K-naive patients, he added, noting that remissions did not appear to be durable, suggesting a potential overlap in resistance mechanisms between agents.

All told, the most effective therapies for in the postvenetoclax setting included the use of a BTK inhibitor in BTK inhibitor–naive or previously responsive patients, and allogeneic transplant following double novel-agent exposure.

“These data may provide support for venetoclax’s earlier use in the course of CLL, and may guide clinical practice and aid in the design of future clinical trials to address sequencing of novel agents,” Dr. Mato told attendees.

While prospective and real-world data clearly show that venetoclax is active in ibrutinib- or idelalisib-exposed patients, data are conversely “variable and limited” with regard to outcomes for next therapies following venetoclax.

“Current data addressing this key sequencing question, I feel, is a major limitation in supporting the sequence of venetoclax to a BTK inhibitor,” Dr. Mato said.

Accordingly, Dr. Mato and colleagues at 31 centers internationally planned and conducted this study, which included data on 326 patients treated with venetoclax who then discontinued for any reason.

“I wanted to highlight that 50% of the sites for this trial were recruited by a single tweet,” said Dr. Mato, adding that he and his coauthors received no funding to conduct this study and volunteered their time to complete it.

They found that, in BTK inhibitor–naive patients who discontinued venetoclax, subsequent BTK inhibitor treatment was associated with a high overall response rate and durable remissions, with a median progression-free survival (PFS) of 32 months.

In BTK inhibitor–exposed patients, response to postvenetoclax BTK inhibitor treatment depended on the reason for discontinuation, with a favorable result (PFS not reached with a mean follow-up of 7.7 months) in patients who were intolerant of the prior BTK inhibitor. By contrast, median PFS was only about 4 months for patients who were resistant to the prior BTK inhibitor.

PI3K inhibitors did not produce durable remissions after venetoclax, with a median PFS also of just 4 months, Dr. Mato reported.

However, cellular therapies appeared to be effective after venetoclax. Allogeneic hematopoietic stem cell transplantation was particularly effective, with the median PFS not reached, while chimeric antigen receptor T-cell therapy produced a PFS of 9 months.

Dr. Mato emphasized that the results of the retrospective trial were “hypothesis generating” and noted that patients in the study had received a median of 3, and up to 11, prior therapies. “This population are probably not our patients receiving venetoclax in clinical practice. They’re more heavily pretreated.”

Dr. Mato reported disclosures related to Gilead, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, Loxo Oncology, DTRM Biopharma, Genentech, Janssen, Acerta Pharma, Pharmacyclics, and Celgene.

SOURCE: Mato AR et al. ASH 2019, Abstract 502.

ORLANDO – For a patient with chronic lymphocytic leukemia (CLL) who has discontinued venetoclax, choosing the best next therapy may depend on what novel agents the patient was exposed to and why they discontinued them, according to Anthony R. Mato, MD, with the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.

Andrew D. Bowser/MDedge News

If the patient is Bruton tyrosine kinase (BTK) inhibitor naive, then use of a BTK inhibitor after venetoclax would be supported, Dr. Mato said, by the high overall response rates and durable remissions that he and his coinvestigators documented in a retrospective, multicenter study designed specifically to address the gap in knowledge regarding what to use after venetoclax.

If the patient is BTK inhibitor exposed, then the reason for discontinuation needs to be considered before going with that venetoclax-to-BTK inhibitor sequence, Dr. Mato said during an oral presentation at the annual meeting of the American Society of Hematology.

“In patients with resistance to a BTK inhibitor, the sequence was not supported – it did not appear to be effective,” he said. “However, in the setting of intolerance, an alternate BTK inhibitor could be considered.”

The study did not support a venetoclax-to-PI3K inhibitor sequence in PI3K-naive patients, he added, noting that remissions did not appear to be durable, suggesting a potential overlap in resistance mechanisms between agents.

All told, the most effective therapies for in the postvenetoclax setting included the use of a BTK inhibitor in BTK inhibitor–naive or previously responsive patients, and allogeneic transplant following double novel-agent exposure.

“These data may provide support for venetoclax’s earlier use in the course of CLL, and may guide clinical practice and aid in the design of future clinical trials to address sequencing of novel agents,” Dr. Mato told attendees.

While prospective and real-world data clearly show that venetoclax is active in ibrutinib- or idelalisib-exposed patients, data are conversely “variable and limited” with regard to outcomes for next therapies following venetoclax.

“Current data addressing this key sequencing question, I feel, is a major limitation in supporting the sequence of venetoclax to a BTK inhibitor,” Dr. Mato said.

Accordingly, Dr. Mato and colleagues at 31 centers internationally planned and conducted this study, which included data on 326 patients treated with venetoclax who then discontinued for any reason.

“I wanted to highlight that 50% of the sites for this trial were recruited by a single tweet,” said Dr. Mato, adding that he and his coauthors received no funding to conduct this study and volunteered their time to complete it.

They found that, in BTK inhibitor–naive patients who discontinued venetoclax, subsequent BTK inhibitor treatment was associated with a high overall response rate and durable remissions, with a median progression-free survival (PFS) of 32 months.

In BTK inhibitor–exposed patients, response to postvenetoclax BTK inhibitor treatment depended on the reason for discontinuation, with a favorable result (PFS not reached with a mean follow-up of 7.7 months) in patients who were intolerant of the prior BTK inhibitor. By contrast, median PFS was only about 4 months for patients who were resistant to the prior BTK inhibitor.

PI3K inhibitors did not produce durable remissions after venetoclax, with a median PFS also of just 4 months, Dr. Mato reported.

However, cellular therapies appeared to be effective after venetoclax. Allogeneic hematopoietic stem cell transplantation was particularly effective, with the median PFS not reached, while chimeric antigen receptor T-cell therapy produced a PFS of 9 months.

Dr. Mato emphasized that the results of the retrospective trial were “hypothesis generating” and noted that patients in the study had received a median of 3, and up to 11, prior therapies. “This population are probably not our patients receiving venetoclax in clinical practice. They’re more heavily pretreated.”

Dr. Mato reported disclosures related to Gilead, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, Loxo Oncology, DTRM Biopharma, Genentech, Janssen, Acerta Pharma, Pharmacyclics, and Celgene.

SOURCE: Mato AR et al. ASH 2019, Abstract 502.