Cellular Therapy

SAN DIEGO – Ixazomib improved progression-free survival following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma, according to results of a double-blind, randomized, placebo-controlled, phase 3 trial.

Andrew Bowser/MDedge News

Treatment with the oral proteasome inhibitor for 24 months was well tolerated, had a low discontinuation rate, and improved progression-free survival by 39% versus placebo, according to Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens.

These findings suggest ixazomib (Ninlaro) represents a “new treatment option for maintenance after transplantation,” Dr. Dimopoulos said at the annual meeting of the American Society of Hematology.

The trial, known as TOURMALINE-MM3, is the first-ever randomized, double-blind, placebo-controlled study of a proteasome inhibitor used as maintenance after ASCT, according to Dr. Dimopoulos. Lenalidomide is approved in that setting, but 29% of patients who start the treatment discontinue because of treatment-related adverse events.

“Proteasome inhibitors have a different mechanism of action and may provide an alternative to lenalidomide,” Dr. Dimopoulos said at an oral abstract session. Ixazomib has a manageable toxicity profile and “convenient” weekly oral dosing, making it “well suited” for maintenance.

When asked by an attendee whether ixazomib would become “the standard of care” for younger patients with myeloma in this setting, Dr. Dimopoulos replied the results show that ixazomib “is an option for patients, especially for those where a physician may believe that a proteasome inhibitor may be indicated.”

However, when pressed by an attendee to comment on how ixazomib compares with lenalidomide for maintenance, Dr. Dimopoulos remarked that current maintenance studies are moving in the direction of combining therapies.

“I think that instead of saying, ‘is ixazomib better than lenalidomide?’ or vice versa, it is better to see how one may combine those drugs in subsets of patients, or even combine these drugs with other agents,” he said.

The TOURMALINE-MM3 study included 656 patients randomized posttransplantation to receive weekly ixazomib or placebo for up to 2 years.

The median progression-free survival was 26.5 months for ixazomib versus 21.3 months for placebo (P = .002; hazard ratio, 0.720; 95% confidence interval, 0.582-0.890). Median overall survival had not been reached in either ixazomib or placebo arms as of this report, with a median follow-up of 31 months.

The discontinuation rate was 7% for ixazomib versus 5% for placebo, according to the investigator. Moreover, ixazomib was associated with “low toxicity” and no difference in the rates of new primary malignancies, at 3% in both arms.

A manuscript describing results of the TOURMALINE-MM3 study is in press in the Lancet, with an expected online publication date of Dec. 10, Dr. Dimopoulos told attendees. Other studies are ongoing to evaluate ixazomib combinations and treatment to progression in this setting.

TOURMALINE-MM3 is sponsored by Takeda (Millennium), the maker of ixazomib. Dr. Dimopoulos reported honoraria and consultancy with Janssen, Takeda Pharmaceutical, Amgen, Bristol-Myers Squibb, and Celgene.

SOURCE: Dimopoulos MA et al. ASH 2018, Abstract 301.

SAN DIEGO – Ixazomib improved progression-free survival following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma, according to results of a double-blind, randomized, placebo-controlled, phase 3 trial.

Andrew Bowser/MDedge News

Treatment with the oral proteasome inhibitor for 24 months was well tolerated, had a low discontinuation rate, and improved progression-free survival by 39% versus placebo, according to Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens.

These findings suggest ixazomib (Ninlaro) represents a “new treatment option for maintenance after transplantation,” Dr. Dimopoulos said at the annual meeting of the American Society of Hematology.

The trial, known as TOURMALINE-MM3, is the first-ever randomized, double-blind, placebo-controlled study of a proteasome inhibitor used as maintenance after ASCT, according to Dr. Dimopoulos. Lenalidomide is approved in that setting, but 29% of patients who start the treatment discontinue because of treatment-related adverse events.

“Proteasome inhibitors have a different mechanism of action and may provide an alternative to lenalidomide,” Dr. Dimopoulos said at an oral abstract session. Ixazomib has a manageable toxicity profile and “convenient” weekly oral dosing, making it “well suited” for maintenance.

When asked by an attendee whether ixazomib would become “the standard of care” for younger patients with myeloma in this setting, Dr. Dimopoulos replied the results show that ixazomib “is an option for patients, especially for those where a physician may believe that a proteasome inhibitor may be indicated.”

However, when pressed by an attendee to comment on how ixazomib compares with lenalidomide for maintenance, Dr. Dimopoulos remarked that current maintenance studies are moving in the direction of combining therapies.

“I think that instead of saying, ‘is ixazomib better than lenalidomide?’ or vice versa, it is better to see how one may combine those drugs in subsets of patients, or even combine these drugs with other agents,” he said.

The TOURMALINE-MM3 study included 656 patients randomized posttransplantation to receive weekly ixazomib or placebo for up to 2 years.

The median progression-free survival was 26.5 months for ixazomib versus 21.3 months for placebo (P = .002; hazard ratio, 0.720; 95% confidence interval, 0.582-0.890). Median overall survival had not been reached in either ixazomib or placebo arms as of this report, with a median follow-up of 31 months.

The discontinuation rate was 7% for ixazomib versus 5% for placebo, according to the investigator. Moreover, ixazomib was associated with “low toxicity” and no difference in the rates of new primary malignancies, at 3% in both arms.

A manuscript describing results of the TOURMALINE-MM3 study is in press in the Lancet, with an expected online publication date of Dec. 10, Dr. Dimopoulos told attendees. Other studies are ongoing to evaluate ixazomib combinations and treatment to progression in this setting.

TOURMALINE-MM3 is sponsored by Takeda (Millennium), the maker of ixazomib. Dr. Dimopoulos reported honoraria and consultancy with Janssen, Takeda Pharmaceutical, Amgen, Bristol-Myers Squibb, and Celgene.

SOURCE: Dimopoulos MA et al. ASH 2018, Abstract 301.

SAN DIEGO – Ixazomib improved progression-free survival following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma, according to results of a double-blind, randomized, placebo-controlled, phase 3 trial.

Andrew Bowser/MDedge News

Treatment with the oral proteasome inhibitor for 24 months was well tolerated, had a low discontinuation rate, and improved progression-free survival by 39% versus placebo, according to Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens.

These findings suggest ixazomib (Ninlaro) represents a “new treatment option for maintenance after transplantation,” Dr. Dimopoulos said at the annual meeting of the American Society of Hematology.

The trial, known as TOURMALINE-MM3, is the first-ever randomized, double-blind, placebo-controlled study of a proteasome inhibitor used as maintenance after ASCT, according to Dr. Dimopoulos. Lenalidomide is approved in that setting, but 29% of patients who start the treatment discontinue because of treatment-related adverse events.

“Proteasome inhibitors have a different mechanism of action and may provide an alternative to lenalidomide,” Dr. Dimopoulos said at an oral abstract session. Ixazomib has a manageable toxicity profile and “convenient” weekly oral dosing, making it “well suited” for maintenance.

When asked by an attendee whether ixazomib would become “the standard of care” for younger patients with myeloma in this setting, Dr. Dimopoulos replied the results show that ixazomib “is an option for patients, especially for those where a physician may believe that a proteasome inhibitor may be indicated.”

However, when pressed by an attendee to comment on how ixazomib compares with lenalidomide for maintenance, Dr. Dimopoulos remarked that current maintenance studies are moving in the direction of combining therapies.

“I think that instead of saying, ‘is ixazomib better than lenalidomide?’ or vice versa, it is better to see how one may combine those drugs in subsets of patients, or even combine these drugs with other agents,” he said.

The TOURMALINE-MM3 study included 656 patients randomized posttransplantation to receive weekly ixazomib or placebo for up to 2 years.

The median progression-free survival was 26.5 months for ixazomib versus 21.3 months for placebo (P = .002; hazard ratio, 0.720; 95% confidence interval, 0.582-0.890). Median overall survival had not been reached in either ixazomib or placebo arms as of this report, with a median follow-up of 31 months.

The discontinuation rate was 7% for ixazomib versus 5% for placebo, according to the investigator. Moreover, ixazomib was associated with “low toxicity” and no difference in the rates of new primary malignancies, at 3% in both arms.

A manuscript describing results of the TOURMALINE-MM3 study is in press in the Lancet, with an expected online publication date of Dec. 10, Dr. Dimopoulos told attendees. Other studies are ongoing to evaluate ixazomib combinations and treatment to progression in this setting.

TOURMALINE-MM3 is sponsored by Takeda (Millennium), the maker of ixazomib. Dr. Dimopoulos reported honoraria and consultancy with Janssen, Takeda Pharmaceutical, Amgen, Bristol-Myers Squibb, and Celgene.

SOURCE: Dimopoulos MA et al. ASH 2018, Abstract 301.

SAN DIEGO – Two-thirds of adults with relapsed or refractory diffuse large B-cell lymphoma who had early responses to chimeric antigen receptor T-cell (CAR T) therapy with tisagenlecleucel (Kymriah) remain in remission with no evidence of minimal residual disease, according to an updated analysis of the JULIET trial.

In the single-arm, open-label trial, the overall response rate after 19 months of follow-up was 54%, including 40% complete remissions and 14% partial remissions. The median duration of response had not been reached at the time of data cutoff, and the median overall survival had not been reached for patients with a complete remission. Overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months.

Adverse events were similar to those previously reported and were manageable, according to investigator Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute in Portland.

In this video interview at the annual meeting of the American Society of Hematology, Dr. Maziarz discusses the promising results using CAR T cells in this difficult to treat population.

SAN DIEGO – Two-thirds of adults with relapsed or refractory diffuse large B-cell lymphoma who had early responses to chimeric antigen receptor T-cell (CAR T) therapy with tisagenlecleucel (Kymriah) remain in remission with no evidence of minimal residual disease, according to an updated analysis of the JULIET trial.

In the single-arm, open-label trial, the overall response rate after 19 months of follow-up was 54%, including 40% complete remissions and 14% partial remissions. The median duration of response had not been reached at the time of data cutoff, and the median overall survival had not been reached for patients with a complete remission. Overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months.

Adverse events were similar to those previously reported and were manageable, according to investigator Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute in Portland.

In this video interview at the annual meeting of the American Society of Hematology, Dr. Maziarz discusses the promising results using CAR T cells in this difficult to treat population.

SAN DIEGO – Two-thirds of adults with relapsed or refractory diffuse large B-cell lymphoma who had early responses to chimeric antigen receptor T-cell (CAR T) therapy with tisagenlecleucel (Kymriah) remain in remission with no evidence of minimal residual disease, according to an updated analysis of the JULIET trial.

In the single-arm, open-label trial, the overall response rate after 19 months of follow-up was 54%, including 40% complete remissions and 14% partial remissions. The median duration of response had not been reached at the time of data cutoff, and the median overall survival had not been reached for patients with a complete remission. Overall survival in this heavily pretreated population as a whole (all patients who received CAR T-cell infusions) was 11.1 months.

Adverse events were similar to those previously reported and were manageable, according to investigator Richard Thomas Maziarz, MD, from the Oregon Health & Science Knight Cancer Institute in Portland.

In this video interview at the annual meeting of the American Society of Hematology, Dr. Maziarz discusses the promising results using CAR T cells in this difficult to treat population.

SAN DIEGO – Diversity of the gut microbiome, sampled either before or after an allogeneic hematopoietic cell transplant (HCT), is predictive of overall survival.

A multinational study of intestinal microbiota in the United States, Europe, and Japan showed that in all four geographic regions patients scheduled for HCT had about a 100% lower median diversity of intestinal bacteria, compared with healthy volunteers, and that enterococcal species predominated in the transplant candidates, reported Jonathan U. Peled, MD, PhD, from the bone marrow transplantation service at Memorial Sloan Kettering Cancer Center in New York.

The investigators also found that intestinal microbial diversity was significantly associated with overall survival following an HCT.

In a video interview at the annual meeting of the American Society of Hematology, Dr. Peled elaborated on the study findings and described potential pre- and posttransplant interventions that could improve results and increase survival following HCT.

Dr. Peled reported current or prior relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.

SAN DIEGO – Diversity of the gut microbiome, sampled either before or after an allogeneic hematopoietic cell transplant (HCT), is predictive of overall survival.

A multinational study of intestinal microbiota in the United States, Europe, and Japan showed that in all four geographic regions patients scheduled for HCT had about a 100% lower median diversity of intestinal bacteria, compared with healthy volunteers, and that enterococcal species predominated in the transplant candidates, reported Jonathan U. Peled, MD, PhD, from the bone marrow transplantation service at Memorial Sloan Kettering Cancer Center in New York.

The investigators also found that intestinal microbial diversity was significantly associated with overall survival following an HCT.

In a video interview at the annual meeting of the American Society of Hematology, Dr. Peled elaborated on the study findings and described potential pre- and posttransplant interventions that could improve results and increase survival following HCT.

Dr. Peled reported current or prior relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.

SAN DIEGO – Diversity of the gut microbiome, sampled either before or after an allogeneic hematopoietic cell transplant (HCT), is predictive of overall survival.

A multinational study of intestinal microbiota in the United States, Europe, and Japan showed that in all four geographic regions patients scheduled for HCT had about a 100% lower median diversity of intestinal bacteria, compared with healthy volunteers, and that enterococcal species predominated in the transplant candidates, reported Jonathan U. Peled, MD, PhD, from the bone marrow transplantation service at Memorial Sloan Kettering Cancer Center in New York.

The investigators also found that intestinal microbial diversity was significantly associated with overall survival following an HCT.

In a video interview at the annual meeting of the American Society of Hematology, Dr. Peled elaborated on the study findings and described potential pre- and posttransplant interventions that could improve results and increase survival following HCT.

Dr. Peled reported current or prior relationships with Seres Therapeutics, the Parker Institute for Cancer Immunotherapy, and Merck/Society for Immunotherapy of Cancer.

SAN DIEGO – A single infusion of tisagenlecleucel (Kymriah) continues to demonstrate high efficacy a year and a half after pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were enrolled in the pivotal ELIANA trial, Stephan A. Grupp, MD, PhD, reported at a press conference at the annual meeting of the American Society of Hematology.

Neil Osterweil/MDedge News

Of patients in complete remission after receiving the chimeric antigen receptor (CAR) T-cell therapy, 66% were still in remission at 18 months of follow-up and median survival has yet to be reached.

“We think the efficacy is sustained and excellent,” said Dr. Grupp, of the University of Pennsylvania, Philadelphia. “These are durable complete responses even without further therapy. We haven’t reached median duration of response or overall survival, and we can manage toxicity, so I think this is clearly an opportunity for us to treat our patients both in America and across the world.”

The results of ELIANA were the basis for the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-cell ALL in the United States, and for subsequent approvals by health authorities in the European Union, Switzerland, and Canada.

The international, single-arm, open-label, phase 2 ELIANA trial included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T-cell therapy.

The rate of overall remission, defined as the rate of complete remission or complete remission with incomplete blood count recovery, was 82% (65 patients). Among those patients, 66% were still in remission at 18 months, while overall survival was “excellent” at 70%, Dr. Grupp said, and the median overall survival was not reached.

Adverse events prevalence remained relatively unchanged since the previous analyses, according to Dr. Grupp, who added that appropriately trained personnel were able to effectively manage those adverse events across study sites. Cytokine release syndrome (CRS) occurred in 77% of patients. All cases were reversible; 39% received tocilizumab for treatment of CRS with or without other anticytokine therapies; 48% required ICU-level care for CRS, with a median ICU stay of 7 days.

The other most common grade 3/4 nonhematologic adverse events were neutropenia with a body temperature exceeding 38.3° C (62% within 8 weeks of infusion), hypoxia (20%), and hypotension (20%). Grade 3 neurologic effects occurred in 13% of patients, and none had cerebral edema. Based on laboratory results, 43% had grade 3/4 thrombocytopenia and 54% had neutropenia not resolved by day 28; most of these events resolved to grade 2 or less by 3 months.

There were 25 postinfusion deaths, with 2 occurring within 30 days (1 because of disease progression, 1 because of cerebral hemorrhage). Of the 23 deaths after 30 days (range, 53-859 days), 18 were caused by disease progression. The other deaths were caused by encephalitis, systemic mycosis, vasoocclusive hepatobiliary disorder related to allogeneic SCT, bacterial lung infection, and an unknown reason after study withdrawal.

Follow-up is ongoing in the ELIANA study, which is supported by Novartis, the maker of Kymriah.

Dr. Grupp reported research funding from Novartis, consultancy with Novartis, Jazz Pharmaceuticals, and Adaptimmune Therapeutics, and patents or royalties with the University of Pennsylvania.

SOURCE: Grupp SA et al. ASH 2018, Abstract 895.

SAN DIEGO – A single infusion of tisagenlecleucel (Kymriah) continues to demonstrate high efficacy a year and a half after pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were enrolled in the pivotal ELIANA trial, Stephan A. Grupp, MD, PhD, reported at a press conference at the annual meeting of the American Society of Hematology.

Neil Osterweil/MDedge News

Of patients in complete remission after receiving the chimeric antigen receptor (CAR) T-cell therapy, 66% were still in remission at 18 months of follow-up and median survival has yet to be reached.

“We think the efficacy is sustained and excellent,” said Dr. Grupp, of the University of Pennsylvania, Philadelphia. “These are durable complete responses even without further therapy. We haven’t reached median duration of response or overall survival, and we can manage toxicity, so I think this is clearly an opportunity for us to treat our patients both in America and across the world.”

The results of ELIANA were the basis for the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-cell ALL in the United States, and for subsequent approvals by health authorities in the European Union, Switzerland, and Canada.

The international, single-arm, open-label, phase 2 ELIANA trial included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T-cell therapy.

The rate of overall remission, defined as the rate of complete remission or complete remission with incomplete blood count recovery, was 82% (65 patients). Among those patients, 66% were still in remission at 18 months, while overall survival was “excellent” at 70%, Dr. Grupp said, and the median overall survival was not reached.

Adverse events prevalence remained relatively unchanged since the previous analyses, according to Dr. Grupp, who added that appropriately trained personnel were able to effectively manage those adverse events across study sites. Cytokine release syndrome (CRS) occurred in 77% of patients. All cases were reversible; 39% received tocilizumab for treatment of CRS with or without other anticytokine therapies; 48% required ICU-level care for CRS, with a median ICU stay of 7 days.

The other most common grade 3/4 nonhematologic adverse events were neutropenia with a body temperature exceeding 38.3° C (62% within 8 weeks of infusion), hypoxia (20%), and hypotension (20%). Grade 3 neurologic effects occurred in 13% of patients, and none had cerebral edema. Based on laboratory results, 43% had grade 3/4 thrombocytopenia and 54% had neutropenia not resolved by day 28; most of these events resolved to grade 2 or less by 3 months.

There were 25 postinfusion deaths, with 2 occurring within 30 days (1 because of disease progression, 1 because of cerebral hemorrhage). Of the 23 deaths after 30 days (range, 53-859 days), 18 were caused by disease progression. The other deaths were caused by encephalitis, systemic mycosis, vasoocclusive hepatobiliary disorder related to allogeneic SCT, bacterial lung infection, and an unknown reason after study withdrawal.

Follow-up is ongoing in the ELIANA study, which is supported by Novartis, the maker of Kymriah.

Dr. Grupp reported research funding from Novartis, consultancy with Novartis, Jazz Pharmaceuticals, and Adaptimmune Therapeutics, and patents or royalties with the University of Pennsylvania.

SOURCE: Grupp SA et al. ASH 2018, Abstract 895.

SAN DIEGO – A single infusion of tisagenlecleucel (Kymriah) continues to demonstrate high efficacy a year and a half after pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (ALL) were enrolled in the pivotal ELIANA trial, Stephan A. Grupp, MD, PhD, reported at a press conference at the annual meeting of the American Society of Hematology.

Neil Osterweil/MDedge News

Of patients in complete remission after receiving the chimeric antigen receptor (CAR) T-cell therapy, 66% were still in remission at 18 months of follow-up and median survival has yet to be reached.

“We think the efficacy is sustained and excellent,” said Dr. Grupp, of the University of Pennsylvania, Philadelphia. “These are durable complete responses even without further therapy. We haven’t reached median duration of response or overall survival, and we can manage toxicity, so I think this is clearly an opportunity for us to treat our patients both in America and across the world.”

The results of ELIANA were the basis for the approval of tisagenlecleucel (Kymriah) for relapsed/refractory B-cell ALL in the United States, and for subsequent approvals by health authorities in the European Union, Switzerland, and Canada.

The international, single-arm, open-label, phase 2 ELIANA trial included 97 patients aged 3-24 years with relapsed or refractory B-cell ALL, most of whom had previously undergone a hematopoietic stem cell transplant. Of those patients, 79 patients went on to receive a single infusion of the CAR T-cell therapy.

The rate of overall remission, defined as the rate of complete remission or complete remission with incomplete blood count recovery, was 82% (65 patients). Among those patients, 66% were still in remission at 18 months, while overall survival was “excellent” at 70%, Dr. Grupp said, and the median overall survival was not reached.

Adverse events prevalence remained relatively unchanged since the previous analyses, according to Dr. Grupp, who added that appropriately trained personnel were able to effectively manage those adverse events across study sites. Cytokine release syndrome (CRS) occurred in 77% of patients. All cases were reversible; 39% received tocilizumab for treatment of CRS with or without other anticytokine therapies; 48% required ICU-level care for CRS, with a median ICU stay of 7 days.

The other most common grade 3/4 nonhematologic adverse events were neutropenia with a body temperature exceeding 38.3° C (62% within 8 weeks of infusion), hypoxia (20%), and hypotension (20%). Grade 3 neurologic effects occurred in 13% of patients, and none had cerebral edema. Based on laboratory results, 43% had grade 3/4 thrombocytopenia and 54% had neutropenia not resolved by day 28; most of these events resolved to grade 2 or less by 3 months.

There were 25 postinfusion deaths, with 2 occurring within 30 days (1 because of disease progression, 1 because of cerebral hemorrhage). Of the 23 deaths after 30 days (range, 53-859 days), 18 were caused by disease progression. The other deaths were caused by encephalitis, systemic mycosis, vasoocclusive hepatobiliary disorder related to allogeneic SCT, bacterial lung infection, and an unknown reason after study withdrawal.

Follow-up is ongoing in the ELIANA study, which is supported by Novartis, the maker of Kymriah.

Dr. Grupp reported research funding from Novartis, consultancy with Novartis, Jazz Pharmaceuticals, and Adaptimmune Therapeutics, and patents or royalties with the University of Pennsylvania.

SOURCE: Grupp SA et al. ASH 2018, Abstract 895.

SAN DIEGO – A hematopoietic cell transplant following chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphocytic leukemia (B-ALL) may reduce late relapse risk in certain patients, a retrospective analysis suggests.

Corinne Summers, MD, of Seattle Children’s Hospital, and her colleagues evaluated the potential benefits of allogeneic hematopoietic cell transplant (HCT) in 50 pediatric and young adult B-ALL patients who had sustained leukemic remission after receiving SCRI-CAR19v1, a CD19-specific CAR T-cell product.

Leukemia-free survival was significantly improved for patients with no history of HCT who received CD19 CAR T-cell therapy followed by consolidative HCT, Dr. Summers reported at the annual meeting of the American Society of Hematology.

However, the benefits of consolidative HCT are unclear for patients with a history of HCT, Dr. Summers said at the meeting, noting that larger studies are needed.

In her video interview at ASH 2018, Dr. Summers talked more about the challenges of late leukemic relapse and the potential role of HCT after CAR T-cell therapy.

Dr. Summers reported no disclosures related to her presentation.

SAN DIEGO – A hematopoietic cell transplant following chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphocytic leukemia (B-ALL) may reduce late relapse risk in certain patients, a retrospective analysis suggests.

Corinne Summers, MD, of Seattle Children’s Hospital, and her colleagues evaluated the potential benefits of allogeneic hematopoietic cell transplant (HCT) in 50 pediatric and young adult B-ALL patients who had sustained leukemic remission after receiving SCRI-CAR19v1, a CD19-specific CAR T-cell product.

Leukemia-free survival was significantly improved for patients with no history of HCT who received CD19 CAR T-cell therapy followed by consolidative HCT, Dr. Summers reported at the annual meeting of the American Society of Hematology.

However, the benefits of consolidative HCT are unclear for patients with a history of HCT, Dr. Summers said at the meeting, noting that larger studies are needed.

In her video interview at ASH 2018, Dr. Summers talked more about the challenges of late leukemic relapse and the potential role of HCT after CAR T-cell therapy.

Dr. Summers reported no disclosures related to her presentation.

SAN DIEGO – A hematopoietic cell transplant following chimeric antigen receptor (CAR) T-cell therapy for B-cell acute lymphocytic leukemia (B-ALL) may reduce late relapse risk in certain patients, a retrospective analysis suggests.

Corinne Summers, MD, of Seattle Children’s Hospital, and her colleagues evaluated the potential benefits of allogeneic hematopoietic cell transplant (HCT) in 50 pediatric and young adult B-ALL patients who had sustained leukemic remission after receiving SCRI-CAR19v1, a CD19-specific CAR T-cell product.

Leukemia-free survival was significantly improved for patients with no history of HCT who received CD19 CAR T-cell therapy followed by consolidative HCT, Dr. Summers reported at the annual meeting of the American Society of Hematology.

However, the benefits of consolidative HCT are unclear for patients with a history of HCT, Dr. Summers said at the meeting, noting that larger studies are needed.

In her video interview at ASH 2018, Dr. Summers talked more about the challenges of late leukemic relapse and the potential role of HCT after CAR T-cell therapy.

Dr. Summers reported no disclosures related to her presentation.

SAN DIEGO – Researchers were able to “flip the switch” from the adult to fetal form of hemoglobin using autologous stem cells genetically modified to simultaneously induce the fetal form of hemoglobin and decrease sickle hemoglobin.

The advance was announced by investigators at the Dana-Farber Cancer Institute and Boston Children’s Hospital at the annual meeting of the American Society of Hematology. At 6 months of follow-up, one adult patient in the proof-of-concept study has experienced a reversal of the sickle cell phenotype, with no pain episodes or respiratory or neurologic events.

The fetal form of hemoglobin is known to be protective against the signs and symptoms of sickle cell disease, but apart from a few rare exceptions, people with the disorder begin to experience debilitating symptoms as levels of the fetal form begin to decline in early childhood and levels of the adult form of hemoglobin steadily rise.

In this video interview, Erica B. Esrick, MD, from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, describes the novel approach of using RNA interference to knock down a repressor that suppresses expression of gamma globin in sickle cell disease.

SAN DIEGO – Researchers were able to “flip the switch” from the adult to fetal form of hemoglobin using autologous stem cells genetically modified to simultaneously induce the fetal form of hemoglobin and decrease sickle hemoglobin.

The advance was announced by investigators at the Dana-Farber Cancer Institute and Boston Children’s Hospital at the annual meeting of the American Society of Hematology. At 6 months of follow-up, one adult patient in the proof-of-concept study has experienced a reversal of the sickle cell phenotype, with no pain episodes or respiratory or neurologic events.

The fetal form of hemoglobin is known to be protective against the signs and symptoms of sickle cell disease, but apart from a few rare exceptions, people with the disorder begin to experience debilitating symptoms as levels of the fetal form begin to decline in early childhood and levels of the adult form of hemoglobin steadily rise.

In this video interview, Erica B. Esrick, MD, from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, describes the novel approach of using RNA interference to knock down a repressor that suppresses expression of gamma globin in sickle cell disease.

SAN DIEGO – Researchers were able to “flip the switch” from the adult to fetal form of hemoglobin using autologous stem cells genetically modified to simultaneously induce the fetal form of hemoglobin and decrease sickle hemoglobin.

The advance was announced by investigators at the Dana-Farber Cancer Institute and Boston Children’s Hospital at the annual meeting of the American Society of Hematology. At 6 months of follow-up, one adult patient in the proof-of-concept study has experienced a reversal of the sickle cell phenotype, with no pain episodes or respiratory or neurologic events.

The fetal form of hemoglobin is known to be protective against the signs and symptoms of sickle cell disease, but apart from a few rare exceptions, people with the disorder begin to experience debilitating symptoms as levels of the fetal form begin to decline in early childhood and levels of the adult form of hemoglobin steadily rise.

In this video interview, Erica B. Esrick, MD, from the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, describes the novel approach of using RNA interference to knock down a repressor that suppresses expression of gamma globin in sickle cell disease.

About one in seven patients with newly diagnosed multiple myeloma who are eligible for transplant are living at least as long as similar individuals in the general population, finds a retrospective cohort study of the International Myeloma Working Group. That figure may be even higher today because more than 90% of patients in the study – the largest yet to look at outcome predictors in this population – were treated in the era before novel therapies became available.

Investigators led by Saad Z. Usmani, MD, director/chief of plasma cell disorders and director of clinical research (hematologic malignancies) at the Levine Cancer Institute/Atrium Health in Charlotte, N.C., studied 7,291 patients with newly diagnosed multiple myeloma who were up to 75 years old and eligible for high-dose melphalan and autologous stem cell transplant. The patients were treated in clinical trials in 10 countries.

Compared with counterparts who did not achieve complete response 1 year after diagnosis, patients who did had better median progression-free survival (3.3 vs. 2.6 years; P less than .0001) and median overall survival (8.5 vs. 6.3 years; P less than .0001), according to study results report in Blood Cancer Journal.

The investigators next performed multivariate analyses to assess clinical variables at diagnosis associated with 10-year survival as compared with 2-year death.

Results here indicated that patients were less likely to be alive at 10 years if they were older than 65 years (odds ratio for death, 1.87; P = .002); had an immunoglobulin A isotype (OR, 1.53; P = .004); had a low albumin level, defined as less than 3.5 g/dL (OR, 1.36; P = .023); had an elevated beta₂-microglobulin level, defined as at least 3.5 mg/dL (OR, 1.86; P less than .001); had a higher serum creatinine level, defined as at least 2 mg/dL (OR, 1.77; P = .005); had a lower hemoglobin level, defined as less than 10 g/dL (OR, 1.55; P = .003); or had a lower platelet count, defined as less than 150,000/μL (OR, 2.26; P less than .001).

Cytogenetic abnormalities did not independently predict long-term survival, but these abnormalities were obtained only by conventional band karyotyping and were not available for some patients.

Overall, the cohort had a relative survival of about 0.9 when compared with the matched general population. With follow-up out to about 20 years, the cure fraction (proportion achieving or exceeding expected survival when compared with the matched general population) was 14.3%.

Identification of early complete response as a predictor of long-term survival “underscores the importance of depth of response as we explore novel regimens for newly diagnosed [multiple myeloma] along with [minimal residual disease] endpoints,” Dr. Usmani and his colleagues wrote while acknowledging that the patients studied were a selected group eligible for transplant and treated on trials.

Recent therapeutic advances “have reignited the debate on possible functional curability of a subset MM patients,” they noted. “[T]here are perhaps more effective drugs and drug classes in the clinician’s armamentarium than [were] available for MM patients being treated in the 1990s or even early 2000s. This may mean that the depth of response after induction therapy may continue to improve over time, potentially further improving the PFS/OS of [the] biologic subset who previously achieved [partial response] yet had good long-term survival.”

Dr. Usmani disclosed that he is a consultant for AbbVie, Amgen, BMS, Celgene, Janssen, Takeda, Sanofi, and SkylineDx; receives speaker’s fees for Amgen, Celgene, Janssen, and Takeda; and receives research funding from Amgen, Array Biopharma, BMS, Celgene, Janssen, Pharmacyclics, Sanofi, and Takeda.

SOURCE: Usmani SZ et al. Blood Cancer J. 2018 Nov 23;8(12):123..






 

About one in seven patients with newly diagnosed multiple myeloma who are eligible for transplant are living at least as long as similar individuals in the general population, finds a retrospective cohort study of the International Myeloma Working Group. That figure may be even higher today because more than 90% of patients in the study – the largest yet to look at outcome predictors in this population – were treated in the era before novel therapies became available.

Investigators led by Saad Z. Usmani, MD, director/chief of plasma cell disorders and director of clinical research (hematologic malignancies) at the Levine Cancer Institute/Atrium Health in Charlotte, N.C., studied 7,291 patients with newly diagnosed multiple myeloma who were up to 75 years old and eligible for high-dose melphalan and autologous stem cell transplant. The patients were treated in clinical trials in 10 countries.

Compared with counterparts who did not achieve complete response 1 year after diagnosis, patients who did had better median progression-free survival (3.3 vs. 2.6 years; P less than .0001) and median overall survival (8.5 vs. 6.3 years; P less than .0001), according to study results report in Blood Cancer Journal.

The investigators next performed multivariate analyses to assess clinical variables at diagnosis associated with 10-year survival as compared with 2-year death.

Results here indicated that patients were less likely to be alive at 10 years if they were older than 65 years (odds ratio for death, 1.87; P = .002); had an immunoglobulin A isotype (OR, 1.53; P = .004); had a low albumin level, defined as less than 3.5 g/dL (OR, 1.36; P = .023); had an elevated beta₂-microglobulin level, defined as at least 3.5 mg/dL (OR, 1.86; P less than .001); had a higher serum creatinine level, defined as at least 2 mg/dL (OR, 1.77; P = .005); had a lower hemoglobin level, defined as less than 10 g/dL (OR, 1.55; P = .003); or had a lower platelet count, defined as less than 150,000/μL (OR, 2.26; P less than .001).

Cytogenetic abnormalities did not independently predict long-term survival, but these abnormalities were obtained only by conventional band karyotyping and were not available for some patients.

Overall, the cohort had a relative survival of about 0.9 when compared with the matched general population. With follow-up out to about 20 years, the cure fraction (proportion achieving or exceeding expected survival when compared with the matched general population) was 14.3%.

Identification of early complete response as a predictor of long-term survival “underscores the importance of depth of response as we explore novel regimens for newly diagnosed [multiple myeloma] along with [minimal residual disease] endpoints,” Dr. Usmani and his colleagues wrote while acknowledging that the patients studied were a selected group eligible for transplant and treated on trials.

Recent therapeutic advances “have reignited the debate on possible functional curability of a subset MM patients,” they noted. “[T]here are perhaps more effective drugs and drug classes in the clinician’s armamentarium than [were] available for MM patients being treated in the 1990s or even early 2000s. This may mean that the depth of response after induction therapy may continue to improve over time, potentially further improving the PFS/OS of [the] biologic subset who previously achieved [partial response] yet had good long-term survival.”

Dr. Usmani disclosed that he is a consultant for AbbVie, Amgen, BMS, Celgene, Janssen, Takeda, Sanofi, and SkylineDx; receives speaker’s fees for Amgen, Celgene, Janssen, and Takeda; and receives research funding from Amgen, Array Biopharma, BMS, Celgene, Janssen, Pharmacyclics, Sanofi, and Takeda.

SOURCE: Usmani SZ et al. Blood Cancer J. 2018 Nov 23;8(12):123..






 

About one in seven patients with newly diagnosed multiple myeloma who are eligible for transplant are living at least as long as similar individuals in the general population, finds a retrospective cohort study of the International Myeloma Working Group. That figure may be even higher today because more than 90% of patients in the study – the largest yet to look at outcome predictors in this population – were treated in the era before novel therapies became available.

Investigators led by Saad Z. Usmani, MD, director/chief of plasma cell disorders and director of clinical research (hematologic malignancies) at the Levine Cancer Institute/Atrium Health in Charlotte, N.C., studied 7,291 patients with newly diagnosed multiple myeloma who were up to 75 years old and eligible for high-dose melphalan and autologous stem cell transplant. The patients were treated in clinical trials in 10 countries.

Compared with counterparts who did not achieve complete response 1 year after diagnosis, patients who did had better median progression-free survival (3.3 vs. 2.6 years; P less than .0001) and median overall survival (8.5 vs. 6.3 years; P less than .0001), according to study results report in Blood Cancer Journal.

The investigators next performed multivariate analyses to assess clinical variables at diagnosis associated with 10-year survival as compared with 2-year death.

Results here indicated that patients were less likely to be alive at 10 years if they were older than 65 years (odds ratio for death, 1.87; P = .002); had an immunoglobulin A isotype (OR, 1.53; P = .004); had a low albumin level, defined as less than 3.5 g/dL (OR, 1.36; P = .023); had an elevated beta₂-microglobulin level, defined as at least 3.5 mg/dL (OR, 1.86; P less than .001); had a higher serum creatinine level, defined as at least 2 mg/dL (OR, 1.77; P = .005); had a lower hemoglobin level, defined as less than 10 g/dL (OR, 1.55; P = .003); or had a lower platelet count, defined as less than 150,000/μL (OR, 2.26; P less than .001).

Cytogenetic abnormalities did not independently predict long-term survival, but these abnormalities were obtained only by conventional band karyotyping and were not available for some patients.

Overall, the cohort had a relative survival of about 0.9 when compared with the matched general population. With follow-up out to about 20 years, the cure fraction (proportion achieving or exceeding expected survival when compared with the matched general population) was 14.3%.

Identification of early complete response as a predictor of long-term survival “underscores the importance of depth of response as we explore novel regimens for newly diagnosed [multiple myeloma] along with [minimal residual disease] endpoints,” Dr. Usmani and his colleagues wrote while acknowledging that the patients studied were a selected group eligible for transplant and treated on trials.

Recent therapeutic advances “have reignited the debate on possible functional curability of a subset MM patients,” they noted. “[T]here are perhaps more effective drugs and drug classes in the clinician’s armamentarium than [were] available for MM patients being treated in the 1990s or even early 2000s. This may mean that the depth of response after induction therapy may continue to improve over time, potentially further improving the PFS/OS of [the] biologic subset who previously achieved [partial response] yet had good long-term survival.”

Dr. Usmani disclosed that he is a consultant for AbbVie, Amgen, BMS, Celgene, Janssen, Takeda, Sanofi, and SkylineDx; receives speaker’s fees for Amgen, Celgene, Janssen, and Takeda; and receives research funding from Amgen, Array Biopharma, BMS, Celgene, Janssen, Pharmacyclics, Sanofi, and Takeda.

SOURCE: Usmani SZ et al. Blood Cancer J. 2018 Nov 23;8(12):123..






 

Ibrutinib and checkpoint inhibitors may improve the efficacy of chimeric antigen receptor (CAR) T-cell therapies, according to investigators in two separate studies.

Meanwhile, responses to tisagenlecleucel appear to be even more durable with longer follow-up, according to preliminary results from two more CAR T-cell therapy studies slated for presentation at the annual meeting of the American Society of Hematology.

A fifth study will show that bone marrow transplant may effectively consolidate remission after CAR T-cell therapy, according to Robert A. Brodsky, MD, ASH secretary, who highlighted the studies during a media briefing.

The ibrutinib study (abstract 299) shows that administering this BTK inhibitor starting 2 weeks prior to leukapheresis and continuing until 3 months after JCAR014 could improve responses and may decrease the incidence of severe cytokine release syndrome in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Of 16 patients in an ibrutinib cohort and 18 patients in a no-ibrutinib cohort, the proportion of responders was 88% and 56%, respectively, according to preliminary data reported in the abstract. Grade 3-5 cytokine release syndrome occurred in 5 of 19 patients in the no-ibrutinib cohort, and 0 of 17 patients in the ibrutinib cohort.

Those findings are “early and preliminary, but very exciting” for ibrutinib in combination with this CD-19 specific CAR T-cell therapy said Dr. Brodsky, director of the division of hematology at Johns Hopkins University in Baltimore.

Early results of the checkpoint inhibitor study (abstract 556) suggest that pembrolizumab or nivolumab may augment CD19-directed CAR T-cell therapy in patients with relapsed B-cell acute lymphoblastic leukemia (ALL).

In data to date, 14 patients with early CAR T-cell loss, partial response, or no response to CAR T-cell therapy received a PD-1 inhibitor.

“The idea was if you can give pembrolizumab, you can take the brakes off, and maybe you can reinitiate the immune attack,” Dr. Brodsky said. “Sure enough, they were able to see that in roughly half of the patients. So again, very small, preliminary data, but very exciting that it is safe to give checkpoint inhibitors with CAR T-cells and it may be efficacious at getting the immune response back.”

One of the two tisagenlecleucel updates (abstract 895) showed that in the ELIANA trial, which included pediatric and young adults patients with relapsed/refractory ALL, the probability of relapse-free survival at 18 months was 66%.

“These are some very fast-growing tumors and these are refractory resistant patients, so as we get further and further out, it’s more encouraging to see that there are durable responses,” Dr. Brodsky said.

In the other tisagenlecleucel update (abstract 1684), investigators showed sustained disease control in Juliet, the global trial including adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), with 40% of patients still in remission at 18 months, according to Dr. Brodsky.

One more report Dr. Brodsky highlighted (abstract 967) will look at long-term follow-up after administration of SCRI-CAR19v1, a CD19-specific CAR T-cell product. Preliminary data suggest a survival advantage when hematopoietic stem cell transplantation is done after CAR T-cell induced remission.

“This study is very small and it’s retrospective, but it suggests that bone marrow transplant is a good way to consolidate the remission after CAR T-cell therapy,” Dr. Brodsky said.

Ibrutinib and checkpoint inhibitors may improve the efficacy of chimeric antigen receptor (CAR) T-cell therapies, according to investigators in two separate studies.

Meanwhile, responses to tisagenlecleucel appear to be even more durable with longer follow-up, according to preliminary results from two more CAR T-cell therapy studies slated for presentation at the annual meeting of the American Society of Hematology.

A fifth study will show that bone marrow transplant may effectively consolidate remission after CAR T-cell therapy, according to Robert A. Brodsky, MD, ASH secretary, who highlighted the studies during a media briefing.

The ibrutinib study (abstract 299) shows that administering this BTK inhibitor starting 2 weeks prior to leukapheresis and continuing until 3 months after JCAR014 could improve responses and may decrease the incidence of severe cytokine release syndrome in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Of 16 patients in an ibrutinib cohort and 18 patients in a no-ibrutinib cohort, the proportion of responders was 88% and 56%, respectively, according to preliminary data reported in the abstract. Grade 3-5 cytokine release syndrome occurred in 5 of 19 patients in the no-ibrutinib cohort, and 0 of 17 patients in the ibrutinib cohort.

Those findings are “early and preliminary, but very exciting” for ibrutinib in combination with this CD-19 specific CAR T-cell therapy said Dr. Brodsky, director of the division of hematology at Johns Hopkins University in Baltimore.

Early results of the checkpoint inhibitor study (abstract 556) suggest that pembrolizumab or nivolumab may augment CD19-directed CAR T-cell therapy in patients with relapsed B-cell acute lymphoblastic leukemia (ALL).

In data to date, 14 patients with early CAR T-cell loss, partial response, or no response to CAR T-cell therapy received a PD-1 inhibitor.

“The idea was if you can give pembrolizumab, you can take the brakes off, and maybe you can reinitiate the immune attack,” Dr. Brodsky said. “Sure enough, they were able to see that in roughly half of the patients. So again, very small, preliminary data, but very exciting that it is safe to give checkpoint inhibitors with CAR T-cells and it may be efficacious at getting the immune response back.”

One of the two tisagenlecleucel updates (abstract 895) showed that in the ELIANA trial, which included pediatric and young adults patients with relapsed/refractory ALL, the probability of relapse-free survival at 18 months was 66%.

“These are some very fast-growing tumors and these are refractory resistant patients, so as we get further and further out, it’s more encouraging to see that there are durable responses,” Dr. Brodsky said.

In the other tisagenlecleucel update (abstract 1684), investigators showed sustained disease control in Juliet, the global trial including adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), with 40% of patients still in remission at 18 months, according to Dr. Brodsky.

One more report Dr. Brodsky highlighted (abstract 967) will look at long-term follow-up after administration of SCRI-CAR19v1, a CD19-specific CAR T-cell product. Preliminary data suggest a survival advantage when hematopoietic stem cell transplantation is done after CAR T-cell induced remission.

“This study is very small and it’s retrospective, but it suggests that bone marrow transplant is a good way to consolidate the remission after CAR T-cell therapy,” Dr. Brodsky said.

Ibrutinib and checkpoint inhibitors may improve the efficacy of chimeric antigen receptor (CAR) T-cell therapies, according to investigators in two separate studies.

Meanwhile, responses to tisagenlecleucel appear to be even more durable with longer follow-up, according to preliminary results from two more CAR T-cell therapy studies slated for presentation at the annual meeting of the American Society of Hematology.

A fifth study will show that bone marrow transplant may effectively consolidate remission after CAR T-cell therapy, according to Robert A. Brodsky, MD, ASH secretary, who highlighted the studies during a media briefing.

The ibrutinib study (abstract 299) shows that administering this BTK inhibitor starting 2 weeks prior to leukapheresis and continuing until 3 months after JCAR014 could improve responses and may decrease the incidence of severe cytokine release syndrome in patients with relapsed or refractory chronic lymphocytic leukemia (CLL).

Of 16 patients in an ibrutinib cohort and 18 patients in a no-ibrutinib cohort, the proportion of responders was 88% and 56%, respectively, according to preliminary data reported in the abstract. Grade 3-5 cytokine release syndrome occurred in 5 of 19 patients in the no-ibrutinib cohort, and 0 of 17 patients in the ibrutinib cohort.

Those findings are “early and preliminary, but very exciting” for ibrutinib in combination with this CD-19 specific CAR T-cell therapy said Dr. Brodsky, director of the division of hematology at Johns Hopkins University in Baltimore.

Early results of the checkpoint inhibitor study (abstract 556) suggest that pembrolizumab or nivolumab may augment CD19-directed CAR T-cell therapy in patients with relapsed B-cell acute lymphoblastic leukemia (ALL).

In data to date, 14 patients with early CAR T-cell loss, partial response, or no response to CAR T-cell therapy received a PD-1 inhibitor.

“The idea was if you can give pembrolizumab, you can take the brakes off, and maybe you can reinitiate the immune attack,” Dr. Brodsky said. “Sure enough, they were able to see that in roughly half of the patients. So again, very small, preliminary data, but very exciting that it is safe to give checkpoint inhibitors with CAR T-cells and it may be efficacious at getting the immune response back.”

One of the two tisagenlecleucel updates (abstract 895) showed that in the ELIANA trial, which included pediatric and young adults patients with relapsed/refractory ALL, the probability of relapse-free survival at 18 months was 66%.

“These are some very fast-growing tumors and these are refractory resistant patients, so as we get further and further out, it’s more encouraging to see that there are durable responses,” Dr. Brodsky said.

In the other tisagenlecleucel update (abstract 1684), investigators showed sustained disease control in Juliet, the global trial including adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), with 40% of patients still in remission at 18 months, according to Dr. Brodsky.

One more report Dr. Brodsky highlighted (abstract 967) will look at long-term follow-up after administration of SCRI-CAR19v1, a CD19-specific CAR T-cell product. Preliminary data suggest a survival advantage when hematopoietic stem cell transplantation is done after CAR T-cell induced remission.

“This study is very small and it’s retrospective, but it suggests that bone marrow transplant is a good way to consolidate the remission after CAR T-cell therapy,” Dr. Brodsky said.

CHICAGO – Changes in quantitative lung CT scores for scleroderma-related interstitial lung disease independently validate the superiority of hematopoietic stem cell transplantation versus cyclophosphamide for severe systemic sclerosis, according to findings in a subset of patients from the SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial.

Mitchel L. Zoler/MDedge News

The recently published findings from the SCOT trial showed that myeloablation followed by autologous hematopoietic stem cell transplant (HSCT) significantly improved event-free and overall survival of systemic sclerosis patients at 54 months, compared with 12 monthly treatments with intravenous cyclophosphamide (N Engl J Med. 2018;378:35-47).

In a subset of 75 patients from the SCOT trial, the investigators analyzed changes in lung parenchymal abnormalities on high-resolution CT scans between baseline and serial follow-up exams performed yearly for up to 5 years. Follow-up scans at 14, 26, 48, and 54 months in available patients at each time point showed that whole-lung quantitative interstitial lung disease (QILD) scores – a validated measure that combines various CT texture-based characteristics to determine disease extent – decreased significantly by 7% at 54 months in patients who underwent HSCT, compared with no change in those who received cyclophosphamide (CYC; P = .024), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.

Additionally, whole-lung quantitative lung fibrosis (QLF) scores were stable (–1%) in the HSCT patients, but increased 3% in the CYC patients (P = .047), said Dr. Sullivan, a professor of medicine at Duke University, Durham, N.C.


Dr. Sullivan was the first author on the SCOT trial, and he reported the current study results on behalf of lead investigator Jonathan Goldin, MD, PhD, of the department of radiologic sciences at the University of California, Los Angeles.

“These are really kind of meaningful associations, especially since the worst of the [CYC] treatment group didn’t make it to month 54,” Dr. Sullivan said.

Quantitative scores of scleroderma-related interstitial lung disease were measured using computer-based quantitative image analysis of standardized, noncontrast, volumetric, thin-section, thoracic, high-resolution CT. The same CT machine was used for all time points (except for one subject) with careful attention to breath hold reproducibility and image quality. Baseline characteristics were not different between the HSCT and CYC groups, he noted, stressing the rigorous study design.

CT assessments were also compared for the most severe lobe in each patient and showed similar findings, with both QILD and QLF scores for that lobe improving in the HSCT patients relative to the CYC patients (P = .004 and P = .002, respectively), Dr. Sullivan said, adding that the direction of change in structural measures of QILD and QLF for both whole lung and most severe lobe CTs tracked with physiological pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 second, and diffusing capacity of the lungs for carbon monoxide.

“The FVC improved while QILD decreased, and that’s what you would expect to see,” he said. “So for each of these ways of displaying data, there was an expected and sensible inverse correlation.”

Scleroderma-related interstitial lung disease is a major cause of morbidity and mortality in severe systemic sclerosis. In the wake of the SCOT trial findings, questions remained with respect to correlation between those findings and pulmonary function; if the improvements with HSCT are real and meaningful, they should have meaningful correlation with pulmonary function, and these findings demonstrate those correlates, he said.

“Changes in quantitative lung CT scoring of scleroderma lung disease provide an objective radiologic validation of the long-term benefits of transplant compared to cyclophosphamide in individuals with severe scleroderma and lung involvement. Improvement in imaging after transplant continues for up to 54 months after randomization, giving radiologic confirmation of a durable treatment benefit,” Dr. Sullivan concluded.

The investigators reported having no relevant disclosures.

[email protected]

SOURCE: Goldin J et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 901.

CHICAGO – Changes in quantitative lung CT scores for scleroderma-related interstitial lung disease independently validate the superiority of hematopoietic stem cell transplantation versus cyclophosphamide for severe systemic sclerosis, according to findings in a subset of patients from the SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial.

Mitchel L. Zoler/MDedge News

The recently published findings from the SCOT trial showed that myeloablation followed by autologous hematopoietic stem cell transplant (HSCT) significantly improved event-free and overall survival of systemic sclerosis patients at 54 months, compared with 12 monthly treatments with intravenous cyclophosphamide (N Engl J Med. 2018;378:35-47).

In a subset of 75 patients from the SCOT trial, the investigators analyzed changes in lung parenchymal abnormalities on high-resolution CT scans between baseline and serial follow-up exams performed yearly for up to 5 years. Follow-up scans at 14, 26, 48, and 54 months in available patients at each time point showed that whole-lung quantitative interstitial lung disease (QILD) scores – a validated measure that combines various CT texture-based characteristics to determine disease extent – decreased significantly by 7% at 54 months in patients who underwent HSCT, compared with no change in those who received cyclophosphamide (CYC; P = .024), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.

Additionally, whole-lung quantitative lung fibrosis (QLF) scores were stable (–1%) in the HSCT patients, but increased 3% in the CYC patients (P = .047), said Dr. Sullivan, a professor of medicine at Duke University, Durham, N.C.


Dr. Sullivan was the first author on the SCOT trial, and he reported the current study results on behalf of lead investigator Jonathan Goldin, MD, PhD, of the department of radiologic sciences at the University of California, Los Angeles.

“These are really kind of meaningful associations, especially since the worst of the [CYC] treatment group didn’t make it to month 54,” Dr. Sullivan said.

Quantitative scores of scleroderma-related interstitial lung disease were measured using computer-based quantitative image analysis of standardized, noncontrast, volumetric, thin-section, thoracic, high-resolution CT. The same CT machine was used for all time points (except for one subject) with careful attention to breath hold reproducibility and image quality. Baseline characteristics were not different between the HSCT and CYC groups, he noted, stressing the rigorous study design.

CT assessments were also compared for the most severe lobe in each patient and showed similar findings, with both QILD and QLF scores for that lobe improving in the HSCT patients relative to the CYC patients (P = .004 and P = .002, respectively), Dr. Sullivan said, adding that the direction of change in structural measures of QILD and QLF for both whole lung and most severe lobe CTs tracked with physiological pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 second, and diffusing capacity of the lungs for carbon monoxide.

“The FVC improved while QILD decreased, and that’s what you would expect to see,” he said. “So for each of these ways of displaying data, there was an expected and sensible inverse correlation.”

Scleroderma-related interstitial lung disease is a major cause of morbidity and mortality in severe systemic sclerosis. In the wake of the SCOT trial findings, questions remained with respect to correlation between those findings and pulmonary function; if the improvements with HSCT are real and meaningful, they should have meaningful correlation with pulmonary function, and these findings demonstrate those correlates, he said.

“Changes in quantitative lung CT scoring of scleroderma lung disease provide an objective radiologic validation of the long-term benefits of transplant compared to cyclophosphamide in individuals with severe scleroderma and lung involvement. Improvement in imaging after transplant continues for up to 54 months after randomization, giving radiologic confirmation of a durable treatment benefit,” Dr. Sullivan concluded.

The investigators reported having no relevant disclosures.

[email protected]

SOURCE: Goldin J et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 901.

CHICAGO – Changes in quantitative lung CT scores for scleroderma-related interstitial lung disease independently validate the superiority of hematopoietic stem cell transplantation versus cyclophosphamide for severe systemic sclerosis, according to findings in a subset of patients from the SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial.

Mitchel L. Zoler/MDedge News

The recently published findings from the SCOT trial showed that myeloablation followed by autologous hematopoietic stem cell transplant (HSCT) significantly improved event-free and overall survival of systemic sclerosis patients at 54 months, compared with 12 monthly treatments with intravenous cyclophosphamide (N Engl J Med. 2018;378:35-47).

In a subset of 75 patients from the SCOT trial, the investigators analyzed changes in lung parenchymal abnormalities on high-resolution CT scans between baseline and serial follow-up exams performed yearly for up to 5 years. Follow-up scans at 14, 26, 48, and 54 months in available patients at each time point showed that whole-lung quantitative interstitial lung disease (QILD) scores – a validated measure that combines various CT texture-based characteristics to determine disease extent – decreased significantly by 7% at 54 months in patients who underwent HSCT, compared with no change in those who received cyclophosphamide (CYC; P = .024), Keith M. Sullivan, MD, reported at the annual meeting of the American College of Rheumatology.

Additionally, whole-lung quantitative lung fibrosis (QLF) scores were stable (–1%) in the HSCT patients, but increased 3% in the CYC patients (P = .047), said Dr. Sullivan, a professor of medicine at Duke University, Durham, N.C.


Dr. Sullivan was the first author on the SCOT trial, and he reported the current study results on behalf of lead investigator Jonathan Goldin, MD, PhD, of the department of radiologic sciences at the University of California, Los Angeles.

“These are really kind of meaningful associations, especially since the worst of the [CYC] treatment group didn’t make it to month 54,” Dr. Sullivan said.

Quantitative scores of scleroderma-related interstitial lung disease were measured using computer-based quantitative image analysis of standardized, noncontrast, volumetric, thin-section, thoracic, high-resolution CT. The same CT machine was used for all time points (except for one subject) with careful attention to breath hold reproducibility and image quality. Baseline characteristics were not different between the HSCT and CYC groups, he noted, stressing the rigorous study design.

CT assessments were also compared for the most severe lobe in each patient and showed similar findings, with both QILD and QLF scores for that lobe improving in the HSCT patients relative to the CYC patients (P = .004 and P = .002, respectively), Dr. Sullivan said, adding that the direction of change in structural measures of QILD and QLF for both whole lung and most severe lobe CTs tracked with physiological pulmonary function tests, including forced vital capacity (FVC), forced expiratory volume in 1 second, and diffusing capacity of the lungs for carbon monoxide.

“The FVC improved while QILD decreased, and that’s what you would expect to see,” he said. “So for each of these ways of displaying data, there was an expected and sensible inverse correlation.”

Scleroderma-related interstitial lung disease is a major cause of morbidity and mortality in severe systemic sclerosis. In the wake of the SCOT trial findings, questions remained with respect to correlation between those findings and pulmonary function; if the improvements with HSCT are real and meaningful, they should have meaningful correlation with pulmonary function, and these findings demonstrate those correlates, he said.

“Changes in quantitative lung CT scoring of scleroderma lung disease provide an objective radiologic validation of the long-term benefits of transplant compared to cyclophosphamide in individuals with severe scleroderma and lung involvement. Improvement in imaging after transplant continues for up to 54 months after randomization, giving radiologic confirmation of a durable treatment benefit,” Dr. Sullivan concluded.

The investigators reported having no relevant disclosures.

[email protected]

SOURCE: Goldin J et al. Arthritis Rheumatol. 2018;70(Suppl 10): Abstract 901.

Relapse of acute myeloid leukemia after hematopoietic stem cell transplantation appears to be related to posttransplant changes in immune function that may be reversible with interferon-gamma therapy, investigators said.

Researchers performed a comparison of acute myeloid leukemia (AML) samples taken from patients before hematopoietic stem cell transplantation (HSCT) and at the time of relapse. They found that, while the general genomic changes seen at relapse resembled changes seen when patients experience relapse after chemotherapy, HSCT was associated with changes in genes believed to control both adaptive and innate immunity.

The findings suggest that transplantation results in a dampening of immune surveillance that could potentially be reversed with interferon gamma, an immunostimulatory cytokine, reported Matthew J. Christopher, MD, PhD, from Washington University, St. Louis, and his colleagues.

“These changes appeared to be epigenetic in nature in at least some cases, which suggests that therapeutic strategies to resensitize AML cells to the graft-versus-leukemia effect may be feasible,” they wrote in the New England Journal of Medicine.

The researchers noted that, while the presence of certain AML mutations may predict risk for relapse following HSCT, “the mechanisms by which these mutations promote relapse remain unclear.”

To get a better sense of how genetic and epigenetic changes after transplantation may allow leukemic cells to avoid the graft-versus-leukemia effect – and to see whether immune-related genes are affected by HSCT – they performed enhanced exome sequencing, flow cytometry, and immunohistochemical analyses on samples from 15 patients with AML who had a relapse after receiving transplants from HLA-matched siblings, matched unrelated donors, or HLA-mismatched unrelated donors, and on paired samples from 20 patients who experienced relapses after chemotherapy.

To validate their findings, they also evaluated samples from 28 other patients with AML who had a relapse after transplantation.

They first looked for relapse-specific mutations, but found no driver mutations associated with relapse after transplantation. The mutations seen during relapse after transplantation were generally similar to those seen both before treatment and after relapse in patients who had undergone chemotherapy. The researchers could not identify any patterns of mutations related to relapse.

They then looked for, but did not find, relapse-specific mutations in genes involved in either modulation of immune checkpoints, antigen presentation, or cytokine signaling.

The researchers did, however, find evidence of epigenetic changes that were more common in the samples of patients with posttransplant relapses, compared with postchemotherapy relapses. Specifically, they found that major histocompatibility (MHC) class II genes were down-regulated 200%-1100% after transplant, compared with the pretransplant samples.

In samples from 17 of 34 patients who experienced a relapse after transplantation, both flow cytometry and immunohistochemical analyses confirmed that expression of MHC class II molecules were decreased at relapse.

To see whether this down-regulation was reversible, the researchers treated samples from three patients with posttransplant relapse with interferon gamma, which is known to up-regulate MHC class II protein on myeloid cells and other cell types.

“Culture of these cells with interferon-gamma rapidly induced MHC class II protein expression on leukemic blasts, with essentially full restoration of MHC class II protein expression in nearly all AML blasts after 72 hours,” they wrote, adding that the reversibility of down-regulation of MHC class II in these blasts “strongly suggests that this phenomenon is mediated by an epigenetic mechanism.”

The study was supported by grants to investigators from the National Institutes of Health, Leukemia & Lymphoma Society, and the Barnes-Jewish Hospital Foundation. Dr. Christopher and several coauthors reported receiving grants from the study funders but no other relevant conflicts of interest. Several coauthors reported receiving personal fees and/or research support from industry outside the submitted work.

SOURCE: Christopher MJ et al. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1808777.

Relapse of acute myeloid leukemia after hematopoietic stem cell transplantation appears to be related to posttransplant changes in immune function that may be reversible with interferon-gamma therapy, investigators said.

Researchers performed a comparison of acute myeloid leukemia (AML) samples taken from patients before hematopoietic stem cell transplantation (HSCT) and at the time of relapse. They found that, while the general genomic changes seen at relapse resembled changes seen when patients experience relapse after chemotherapy, HSCT was associated with changes in genes believed to control both adaptive and innate immunity.

The findings suggest that transplantation results in a dampening of immune surveillance that could potentially be reversed with interferon gamma, an immunostimulatory cytokine, reported Matthew J. Christopher, MD, PhD, from Washington University, St. Louis, and his colleagues.

“These changes appeared to be epigenetic in nature in at least some cases, which suggests that therapeutic strategies to resensitize AML cells to the graft-versus-leukemia effect may be feasible,” they wrote in the New England Journal of Medicine.

The researchers noted that, while the presence of certain AML mutations may predict risk for relapse following HSCT, “the mechanisms by which these mutations promote relapse remain unclear.”

To get a better sense of how genetic and epigenetic changes after transplantation may allow leukemic cells to avoid the graft-versus-leukemia effect – and to see whether immune-related genes are affected by HSCT – they performed enhanced exome sequencing, flow cytometry, and immunohistochemical analyses on samples from 15 patients with AML who had a relapse after receiving transplants from HLA-matched siblings, matched unrelated donors, or HLA-mismatched unrelated donors, and on paired samples from 20 patients who experienced relapses after chemotherapy.

To validate their findings, they also evaluated samples from 28 other patients with AML who had a relapse after transplantation.

They first looked for relapse-specific mutations, but found no driver mutations associated with relapse after transplantation. The mutations seen during relapse after transplantation were generally similar to those seen both before treatment and after relapse in patients who had undergone chemotherapy. The researchers could not identify any patterns of mutations related to relapse.

They then looked for, but did not find, relapse-specific mutations in genes involved in either modulation of immune checkpoints, antigen presentation, or cytokine signaling.

The researchers did, however, find evidence of epigenetic changes that were more common in the samples of patients with posttransplant relapses, compared with postchemotherapy relapses. Specifically, they found that major histocompatibility (MHC) class II genes were down-regulated 200%-1100% after transplant, compared with the pretransplant samples.

In samples from 17 of 34 patients who experienced a relapse after transplantation, both flow cytometry and immunohistochemical analyses confirmed that expression of MHC class II molecules were decreased at relapse.

To see whether this down-regulation was reversible, the researchers treated samples from three patients with posttransplant relapse with interferon gamma, which is known to up-regulate MHC class II protein on myeloid cells and other cell types.

“Culture of these cells with interferon-gamma rapidly induced MHC class II protein expression on leukemic blasts, with essentially full restoration of MHC class II protein expression in nearly all AML blasts after 72 hours,” they wrote, adding that the reversibility of down-regulation of MHC class II in these blasts “strongly suggests that this phenomenon is mediated by an epigenetic mechanism.”

The study was supported by grants to investigators from the National Institutes of Health, Leukemia & Lymphoma Society, and the Barnes-Jewish Hospital Foundation. Dr. Christopher and several coauthors reported receiving grants from the study funders but no other relevant conflicts of interest. Several coauthors reported receiving personal fees and/or research support from industry outside the submitted work.

SOURCE: Christopher MJ et al. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1808777.

Relapse of acute myeloid leukemia after hematopoietic stem cell transplantation appears to be related to posttransplant changes in immune function that may be reversible with interferon-gamma therapy, investigators said.

Researchers performed a comparison of acute myeloid leukemia (AML) samples taken from patients before hematopoietic stem cell transplantation (HSCT) and at the time of relapse. They found that, while the general genomic changes seen at relapse resembled changes seen when patients experience relapse after chemotherapy, HSCT was associated with changes in genes believed to control both adaptive and innate immunity.

The findings suggest that transplantation results in a dampening of immune surveillance that could potentially be reversed with interferon gamma, an immunostimulatory cytokine, reported Matthew J. Christopher, MD, PhD, from Washington University, St. Louis, and his colleagues.

“These changes appeared to be epigenetic in nature in at least some cases, which suggests that therapeutic strategies to resensitize AML cells to the graft-versus-leukemia effect may be feasible,” they wrote in the New England Journal of Medicine.

The researchers noted that, while the presence of certain AML mutations may predict risk for relapse following HSCT, “the mechanisms by which these mutations promote relapse remain unclear.”

To get a better sense of how genetic and epigenetic changes after transplantation may allow leukemic cells to avoid the graft-versus-leukemia effect – and to see whether immune-related genes are affected by HSCT – they performed enhanced exome sequencing, flow cytometry, and immunohistochemical analyses on samples from 15 patients with AML who had a relapse after receiving transplants from HLA-matched siblings, matched unrelated donors, or HLA-mismatched unrelated donors, and on paired samples from 20 patients who experienced relapses after chemotherapy.

To validate their findings, they also evaluated samples from 28 other patients with AML who had a relapse after transplantation.

They first looked for relapse-specific mutations, but found no driver mutations associated with relapse after transplantation. The mutations seen during relapse after transplantation were generally similar to those seen both before treatment and after relapse in patients who had undergone chemotherapy. The researchers could not identify any patterns of mutations related to relapse.

They then looked for, but did not find, relapse-specific mutations in genes involved in either modulation of immune checkpoints, antigen presentation, or cytokine signaling.

The researchers did, however, find evidence of epigenetic changes that were more common in the samples of patients with posttransplant relapses, compared with postchemotherapy relapses. Specifically, they found that major histocompatibility (MHC) class II genes were down-regulated 200%-1100% after transplant, compared with the pretransplant samples.

In samples from 17 of 34 patients who experienced a relapse after transplantation, both flow cytometry and immunohistochemical analyses confirmed that expression of MHC class II molecules were decreased at relapse.

To see whether this down-regulation was reversible, the researchers treated samples from three patients with posttransplant relapse with interferon gamma, which is known to up-regulate MHC class II protein on myeloid cells and other cell types.

“Culture of these cells with interferon-gamma rapidly induced MHC class II protein expression on leukemic blasts, with essentially full restoration of MHC class II protein expression in nearly all AML blasts after 72 hours,” they wrote, adding that the reversibility of down-regulation of MHC class II in these blasts “strongly suggests that this phenomenon is mediated by an epigenetic mechanism.”

The study was supported by grants to investigators from the National Institutes of Health, Leukemia & Lymphoma Society, and the Barnes-Jewish Hospital Foundation. Dr. Christopher and several coauthors reported receiving grants from the study funders but no other relevant conflicts of interest. Several coauthors reported receiving personal fees and/or research support from industry outside the submitted work.

SOURCE: Christopher MJ et al. N Engl J Med. 2018 Oct 31. doi: 10.1056/NEJMoa1808777.