Leukemia, Myelodysplasia, Transplantation

CHICAGO – A novel antibody against CD47 – the “do not eat me” protein – is well tolerated and active in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), according to initial results of a phase 1b study.

Combined with azacitidine, the antibody Hu5F9-G4 (5F9) produced an overall response rate of 64% in untreated AML (9 of 14 patients) and 91% in untreated MDS (10 of 11 patients), according to investigator David A. Sallman, MD, of Moffitt Cancer Center, Tampa, Fla.

With a median follow-up of 3.8 months, none of those patients had yet progressed on the 5F9/azacitidine combination, Dr. Sallman reported during a poster presentation at the annual meeting of the American Society of Clinical Oncology.

A maximum tolerated dose of 5F9 plus the hypomethylating agent was not reached in the study, according to the investigators.

“This was a well-tolerated and safe combination, with encouraging efficacy data in this small cohort that hasn’t been followed for too, too long,” Tara L. Lin, MD, of the University of Kansas Cancer Center, Kansas City, said during a poster discussion session.

“Most interesting is the fact that the combination seems to eliminate the leukemia stem cell population in those patients who respond,” she added.

The fact that 5F9 plus azacitidine eradicated leukemia stem cells in responding patients provides a mechanism for potential long-term durability of response, according to Dr. Sallman and his colleagues.

This first-in-class antibody targets CD47, a “do not eat me” macrophage checkpoint that is overexpressed on tumors, enabling immune invasion, they reported.

However, since CD47 is also expressed on older red blood cells, 5F9 is associated with transient anemia in the first cycle of treatment, Dr. Sallman told attendees at the poster discussion session.

“We do mitigate that with a priming dose of 5F9 that saturates these old red blood cells,” he said. “Over time, going along with the response, the patients have marked hemoglobin improvement, and we do not see worsening of other infection-related complications or cytopenias outside of anemia.”

Based on these results, expansion cohorts have been initiated in both AML and MDS, according to the investigators’ report.

When asked if 5F9 could be tolerable as part of more intensive regimens for fit patients, Dr. Sallman said there are a “whole host of combinations” that may possibly make sense.

“How chemotherapies and other novel agents impact these ‘eat me’ signals – I think some of that needs to be further investigated to come up with the most rational combination,” he said during a question and answer session.

Research funding for the study came from Forty Seven and the California Institute for Regenerative Medicine. Dr. Salman reported having no relationships to disclose. Study coauthors reported relationships with Abbvie, Agios, Celgene, Incyte, and Novartis, among other companies.

SOURCE: Sallman DA et al. ASCO 2019, Abstract 7009.

CHICAGO – A novel antibody against CD47 – the “do not eat me” protein – is well tolerated and active in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), according to initial results of a phase 1b study.

Combined with azacitidine, the antibody Hu5F9-G4 (5F9) produced an overall response rate of 64% in untreated AML (9 of 14 patients) and 91% in untreated MDS (10 of 11 patients), according to investigator David A. Sallman, MD, of Moffitt Cancer Center, Tampa, Fla.

With a median follow-up of 3.8 months, none of those patients had yet progressed on the 5F9/azacitidine combination, Dr. Sallman reported during a poster presentation at the annual meeting of the American Society of Clinical Oncology.

A maximum tolerated dose of 5F9 plus the hypomethylating agent was not reached in the study, according to the investigators.

“This was a well-tolerated and safe combination, with encouraging efficacy data in this small cohort that hasn’t been followed for too, too long,” Tara L. Lin, MD, of the University of Kansas Cancer Center, Kansas City, said during a poster discussion session.

“Most interesting is the fact that the combination seems to eliminate the leukemia stem cell population in those patients who respond,” she added.

The fact that 5F9 plus azacitidine eradicated leukemia stem cells in responding patients provides a mechanism for potential long-term durability of response, according to Dr. Sallman and his colleagues.

This first-in-class antibody targets CD47, a “do not eat me” macrophage checkpoint that is overexpressed on tumors, enabling immune invasion, they reported.

However, since CD47 is also expressed on older red blood cells, 5F9 is associated with transient anemia in the first cycle of treatment, Dr. Sallman told attendees at the poster discussion session.

“We do mitigate that with a priming dose of 5F9 that saturates these old red blood cells,” he said. “Over time, going along with the response, the patients have marked hemoglobin improvement, and we do not see worsening of other infection-related complications or cytopenias outside of anemia.”

Based on these results, expansion cohorts have been initiated in both AML and MDS, according to the investigators’ report.

When asked if 5F9 could be tolerable as part of more intensive regimens for fit patients, Dr. Sallman said there are a “whole host of combinations” that may possibly make sense.

“How chemotherapies and other novel agents impact these ‘eat me’ signals – I think some of that needs to be further investigated to come up with the most rational combination,” he said during a question and answer session.

Research funding for the study came from Forty Seven and the California Institute for Regenerative Medicine. Dr. Salman reported having no relationships to disclose. Study coauthors reported relationships with Abbvie, Agios, Celgene, Incyte, and Novartis, among other companies.

SOURCE: Sallman DA et al. ASCO 2019, Abstract 7009.

CHICAGO – A novel antibody against CD47 – the “do not eat me” protein – is well tolerated and active in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), according to initial results of a phase 1b study.

Combined with azacitidine, the antibody Hu5F9-G4 (5F9) produced an overall response rate of 64% in untreated AML (9 of 14 patients) and 91% in untreated MDS (10 of 11 patients), according to investigator David A. Sallman, MD, of Moffitt Cancer Center, Tampa, Fla.

With a median follow-up of 3.8 months, none of those patients had yet progressed on the 5F9/azacitidine combination, Dr. Sallman reported during a poster presentation at the annual meeting of the American Society of Clinical Oncology.

A maximum tolerated dose of 5F9 plus the hypomethylating agent was not reached in the study, according to the investigators.

“This was a well-tolerated and safe combination, with encouraging efficacy data in this small cohort that hasn’t been followed for too, too long,” Tara L. Lin, MD, of the University of Kansas Cancer Center, Kansas City, said during a poster discussion session.

“Most interesting is the fact that the combination seems to eliminate the leukemia stem cell population in those patients who respond,” she added.

The fact that 5F9 plus azacitidine eradicated leukemia stem cells in responding patients provides a mechanism for potential long-term durability of response, according to Dr. Sallman and his colleagues.

This first-in-class antibody targets CD47, a “do not eat me” macrophage checkpoint that is overexpressed on tumors, enabling immune invasion, they reported.

However, since CD47 is also expressed on older red blood cells, 5F9 is associated with transient anemia in the first cycle of treatment, Dr. Sallman told attendees at the poster discussion session.

“We do mitigate that with a priming dose of 5F9 that saturates these old red blood cells,” he said. “Over time, going along with the response, the patients have marked hemoglobin improvement, and we do not see worsening of other infection-related complications or cytopenias outside of anemia.”

Based on these results, expansion cohorts have been initiated in both AML and MDS, according to the investigators’ report.

When asked if 5F9 could be tolerable as part of more intensive regimens for fit patients, Dr. Sallman said there are a “whole host of combinations” that may possibly make sense.

“How chemotherapies and other novel agents impact these ‘eat me’ signals – I think some of that needs to be further investigated to come up with the most rational combination,” he said during a question and answer session.

Research funding for the study came from Forty Seven and the California Institute for Regenerative Medicine. Dr. Salman reported having no relationships to disclose. Study coauthors reported relationships with Abbvie, Agios, Celgene, Incyte, and Novartis, among other companies.

SOURCE: Sallman DA et al. ASCO 2019, Abstract 7009.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

CHICAGO – A fixed-duration venetoclax-obinutuzumab regimen is safe and provides a superior outcome versus standard chlorambucil-obinutuzumab in elderly patients with untreated chronic lymphocytic leukemia (CLL) and comorbidities, results of a randomized phase 3 trial showed.

At 24 months, progression-free survival was 88.2% for the venetoclax-obinutuzumab regimen, versus 64.1% for chlorambucil-obinutuzumab (hazard ratio, 0.35; 95% confidence interval, 0.23-0.53; P less than .0001) in CLL-14, an open-label, multinational trial presented at the annual meeting of the American Society of Clinical Oncology.

The regimen, given for just 12 28-day cycles, also achieved the highest rate of minimal residual disease (MRD)-negative responses ever seen in a randomized prospective CLL study, according to investigator Kirsten Fischer, MD, of the University of Cologne in Germany.

“We really think that these unprecedented MRD negativity levels will eventually translate into an improved overall survival,” Dr. Fischer said during an oral abstract presentation.

Matthew Steven Davids, MD, of Dana-Farber Cancer Institute/Harvard Medical School, Boston, said venetoclax plus obinutuzumab offers the potential for 1-year, time-limited therapy, which limits concerns over long-term adherence and has the potential for cost savings, should the therapy prove to be highly durable with further follow-up.

“A limitation of the study is that the comparator arm – chlorambucil plus obinutuzumab – is directly applicable to only a relatively small subset of our older and frailer CLL patients,” Dr. Davids said during a podium discussion of the results.

“But nonetheless, venetoclax plus obinutuzumab is a promising, time-limited regimen, and CLL14 is an immediately practice-changing study for frontline CLL treatment,” he added.

The regimen stands in contrast to ibrutinib, which offers durable responses but requires continuous dosing, and FCR (fludarabine, cyclophosphamide, and rituximab), a time-limited therapy with curative potential that is restricted to younger patients with IGHV-mutated CLL, according to Dr. Davids.

In CLL-14, 432 patients were randomized 1:1 to receive venetoclax-obinutuzumab for six cycles followed by venetoclax for six cycles, or chlorambucil-obinutuzumab for six cycles followed by chlorambucil for six cycles. The median age was 72 years in the venetoclax-obinutuzumab arm and 71 years in the chlorambucil-obinutuzumab arm.

The overall response rate was 85% for venetoclax-obinutuzumab and 71% for chlorambucil-obinutuzumab (P = .0007), Dr. Fischer reported at the meeting.

The improvement in progression-free survival seen in the overall study population was also seen in patients with TP53 deletions or mutations, and in those with unmutated IGHV, Dr. Fischer reported.

Rates of MRD negativity in peripheral blood were 76% versus 35% for the venetoclax- and chlorambucil-containing combinations, respectively (P less than .001), and similarly, MRD negativity in bone marrow was 57% versus 17% (P less than .001), she said.

There were no significant differences in the rates of grade 3 or 4 neutropenia, which occurred in 52.8% of the venetoclax–obinutuzumab treated patients and 48.1% of the chlorambucil-obinutuzumab treated patients, or in grade 3 or 4 infections, which occurred in 17.5% and 15.0%, respectively, according to a report, published simultaneously in the New England Journal of Medicine (2019;380:2225-36).

Likewise, all-cause mortality was not significantly different between the arms, at 9.3% and 7.9%, respectively.

F. Hoffmann-La Roche and AbbVie supported the study. Dr. Fischer reported travel, accommodations, or expenses from Roche in her abstract disclosure.

SOURCE: Fischer K et al. ASCO 2019, Abstract 7502.

CHICAGO – Calaspargase pegol (SC-PEG) produces similar outcomes as standard pegaspargase in pediatric and young adult patients with newly diagnosed acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), according to a phase 2 trial.

Jennifer Smith/MDedge News

Patients who received SC-PEG every 3 weeks had similar serum asparaginase activity (SAA), toxicities, and survival rates as patients who received standard pegaspargase every 2 weeks.

Lynda M. Vrooman, MD, of Dana-Farber Cancer Institute in Boston, presented these results at the annual meeting of the American Society of Clinical Oncology.

The trial (NCT01574274) enrolled 239 patients, 230 with ALL and 9 with LL. Most patients had B-cell (n = 207) disease. The patients’ median age was 5.2 years (range, 1.0-20.9 years).

“There were no differences in presenting features by randomization,” Dr. Vrooman noted.

The patients were randomized to receive pegaspargase (n = 120) or SC-PEG (n = 119), a pegylated asparaginase formulation with longer half-life. SC-PEG was given at 2,500 IU/m² every 3 weeks, and pegaspargase was given at 2,500 IU/m² every 2 weeks.

Either asparaginase product was given as part of a 4-week induction regimen (vincristine, prednisone, doxorubicin, and methotrexate), a 3-week intensification regimen (intrathecal chemotherapy with or without radiotherapy) for central nervous system disease, and a 27-week second consolidation regimen (mercaptopurine, methotrexate, and, in high-risk patients, doxorubicin).

SAA

The researchers observed significantly longer SAA with SC-PEG during induction but not after.

During induction, at 25 days after the first asparaginase dose, 88% of patients on SC-PEG and 17% of those on pegaspargase had SAA of at least 0.10 IU/mL (P less than .001). Post-induction, at week 25, 100% of patients in each group had a nadir SAA of at least 0.10 IU/mL.

“The high nadir serum asparaginase activity levels observed for both preparations suggest dosing strategies could be further optimized,” Dr. Vrooman noted.

Safety

There were no significant differences in adverse events between the SC-PEG and pegaspargase arms during or after induction.

Adverse events during induction (in the SC-PEG and pegaspargase arms, respectively) included grade 2 or higher asparaginase allergy (0% and 1%), grade 2 or higher pancreatitis (3% in both), grade 2 or higher thrombosis (3% and 9%), grade 4 hyperbilirubinemia (3% and 1%), grade 3 or higher bacterial infection (12% and 9%), and grade 3 or higher fungal infection (4% and 5%).

Adverse events after induction (in the SC-PEG and pegaspargase arms, respectively) included grade 2 or higher asparaginase allergy (17% and 14%), grade 2 or higher pancreatitis (15% in both), grade 2 or higher thrombosis (18% and 13%), grade 4 hyperbilirubinemia (4% and 3%), grade 3 or higher bacterial infection (12% and 15%), grade 3 or higher fungal infection (2% and 1%), grade 2 or higher bone fracture (3% and 8%), and grade 2 or higher osteonecrosis (3% and 4%).

Response and survival

The complete response rate was 95% (109/115) in the SC-PEG arm and 99% (114/115) in the pegaspargase arm. Rates of induction failure were 3% (n = 4) and 1% (n = 1), respectively, and rates of relapse were 3% (n = 5) and 8% (n = 10), respectively.

There were two induction deaths and two remission deaths in the SC-PEG arm but no induction or remission deaths in the pegaspargase arm.

The median follow-up was 4 years. The 4-year event-free survival rate was 87.7% with SC-PEG and 90.2% with pegaspargase (P = .78). The 4-year overall survival rate was 94.8% and 95.6%, respectively (P = .74).

In closing, Dr. Vrooman said these data suggest SC-PEG provides similar results as standard pegaspargase. She noted that these data informed the U.S. approval of SC-PEG for pediatric and young adult ALL.

This trial was sponsored by the Dana-Farber Cancer Institute in collaboration with Shire and the National Cancer Institute. Dr. Vrooman said she had no relationships to disclose.

[email protected]

SOURCE: Vrooman LM et al. ASCO 2019. Abstract 10006.

CHICAGO – Calaspargase pegol (SC-PEG) produces similar outcomes as standard pegaspargase in pediatric and young adult patients with newly diagnosed acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), according to a phase 2 trial.

Jennifer Smith/MDedge News

Patients who received SC-PEG every 3 weeks had similar serum asparaginase activity (SAA), toxicities, and survival rates as patients who received standard pegaspargase every 2 weeks.

Lynda M. Vrooman, MD, of Dana-Farber Cancer Institute in Boston, presented these results at the annual meeting of the American Society of Clinical Oncology.

The trial (NCT01574274) enrolled 239 patients, 230 with ALL and 9 with LL. Most patients had B-cell (n = 207) disease. The patients’ median age was 5.2 years (range, 1.0-20.9 years).

“There were no differences in presenting features by randomization,” Dr. Vrooman noted.

The patients were randomized to receive pegaspargase (n = 120) or SC-PEG (n = 119), a pegylated asparaginase formulation with longer half-life. SC-PEG was given at 2,500 IU/m² every 3 weeks, and pegaspargase was given at 2,500 IU/m² every 2 weeks.

Either asparaginase product was given as part of a 4-week induction regimen (vincristine, prednisone, doxorubicin, and methotrexate), a 3-week intensification regimen (intrathecal chemotherapy with or without radiotherapy) for central nervous system disease, and a 27-week second consolidation regimen (mercaptopurine, methotrexate, and, in high-risk patients, doxorubicin).

SAA

The researchers observed significantly longer SAA with SC-PEG during induction but not after.

During induction, at 25 days after the first asparaginase dose, 88% of patients on SC-PEG and 17% of those on pegaspargase had SAA of at least 0.10 IU/mL (P less than .001). Post-induction, at week 25, 100% of patients in each group had a nadir SAA of at least 0.10 IU/mL.

“The high nadir serum asparaginase activity levels observed for both preparations suggest dosing strategies could be further optimized,” Dr. Vrooman noted.

Safety

There were no significant differences in adverse events between the SC-PEG and pegaspargase arms during or after induction.

Adverse events during induction (in the SC-PEG and pegaspargase arms, respectively) included grade 2 or higher asparaginase allergy (0% and 1%), grade 2 or higher pancreatitis (3% in both), grade 2 or higher thrombosis (3% and 9%), grade 4 hyperbilirubinemia (3% and 1%), grade 3 or higher bacterial infection (12% and 9%), and grade 3 or higher fungal infection (4% and 5%).

Adverse events after induction (in the SC-PEG and pegaspargase arms, respectively) included grade 2 or higher asparaginase allergy (17% and 14%), grade 2 or higher pancreatitis (15% in both), grade 2 or higher thrombosis (18% and 13%), grade 4 hyperbilirubinemia (4% and 3%), grade 3 or higher bacterial infection (12% and 15%), grade 3 or higher fungal infection (2% and 1%), grade 2 or higher bone fracture (3% and 8%), and grade 2 or higher osteonecrosis (3% and 4%).

Response and survival

The complete response rate was 95% (109/115) in the SC-PEG arm and 99% (114/115) in the pegaspargase arm. Rates of induction failure were 3% (n = 4) and 1% (n = 1), respectively, and rates of relapse were 3% (n = 5) and 8% (n = 10), respectively.

There were two induction deaths and two remission deaths in the SC-PEG arm but no induction or remission deaths in the pegaspargase arm.

The median follow-up was 4 years. The 4-year event-free survival rate was 87.7% with SC-PEG and 90.2% with pegaspargase (P = .78). The 4-year overall survival rate was 94.8% and 95.6%, respectively (P = .74).

In closing, Dr. Vrooman said these data suggest SC-PEG provides similar results as standard pegaspargase. She noted that these data informed the U.S. approval of SC-PEG for pediatric and young adult ALL.

This trial was sponsored by the Dana-Farber Cancer Institute in collaboration with Shire and the National Cancer Institute. Dr. Vrooman said she had no relationships to disclose.

[email protected]

SOURCE: Vrooman LM et al. ASCO 2019. Abstract 10006.

CHICAGO – Calaspargase pegol (SC-PEG) produces similar outcomes as standard pegaspargase in pediatric and young adult patients with newly diagnosed acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL), according to a phase 2 trial.

Jennifer Smith/MDedge News

Patients who received SC-PEG every 3 weeks had similar serum asparaginase activity (SAA), toxicities, and survival rates as patients who received standard pegaspargase every 2 weeks.

Lynda M. Vrooman, MD, of Dana-Farber Cancer Institute in Boston, presented these results at the annual meeting of the American Society of Clinical Oncology.

The trial (NCT01574274) enrolled 239 patients, 230 with ALL and 9 with LL. Most patients had B-cell (n = 207) disease. The patients’ median age was 5.2 years (range, 1.0-20.9 years).

“There were no differences in presenting features by randomization,” Dr. Vrooman noted.

The patients were randomized to receive pegaspargase (n = 120) or SC-PEG (n = 119), a pegylated asparaginase formulation with longer half-life. SC-PEG was given at 2,500 IU/m² every 3 weeks, and pegaspargase was given at 2,500 IU/m² every 2 weeks.

Either asparaginase product was given as part of a 4-week induction regimen (vincristine, prednisone, doxorubicin, and methotrexate), a 3-week intensification regimen (intrathecal chemotherapy with or without radiotherapy) for central nervous system disease, and a 27-week second consolidation regimen (mercaptopurine, methotrexate, and, in high-risk patients, doxorubicin).

SAA

The researchers observed significantly longer SAA with SC-PEG during induction but not after.

During induction, at 25 days after the first asparaginase dose, 88% of patients on SC-PEG and 17% of those on pegaspargase had SAA of at least 0.10 IU/mL (P less than .001). Post-induction, at week 25, 100% of patients in each group had a nadir SAA of at least 0.10 IU/mL.

“The high nadir serum asparaginase activity levels observed for both preparations suggest dosing strategies could be further optimized,” Dr. Vrooman noted.

Safety

There were no significant differences in adverse events between the SC-PEG and pegaspargase arms during or after induction.

Adverse events during induction (in the SC-PEG and pegaspargase arms, respectively) included grade 2 or higher asparaginase allergy (0% and 1%), grade 2 or higher pancreatitis (3% in both), grade 2 or higher thrombosis (3% and 9%), grade 4 hyperbilirubinemia (3% and 1%), grade 3 or higher bacterial infection (12% and 9%), and grade 3 or higher fungal infection (4% and 5%).

Adverse events after induction (in the SC-PEG and pegaspargase arms, respectively) included grade 2 or higher asparaginase allergy (17% and 14%), grade 2 or higher pancreatitis (15% in both), grade 2 or higher thrombosis (18% and 13%), grade 4 hyperbilirubinemia (4% and 3%), grade 3 or higher bacterial infection (12% and 15%), grade 3 or higher fungal infection (2% and 1%), grade 2 or higher bone fracture (3% and 8%), and grade 2 or higher osteonecrosis (3% and 4%).

Response and survival

The complete response rate was 95% (109/115) in the SC-PEG arm and 99% (114/115) in the pegaspargase arm. Rates of induction failure were 3% (n = 4) and 1% (n = 1), respectively, and rates of relapse were 3% (n = 5) and 8% (n = 10), respectively.

There were two induction deaths and two remission deaths in the SC-PEG arm but no induction or remission deaths in the pegaspargase arm.

The median follow-up was 4 years. The 4-year event-free survival rate was 87.7% with SC-PEG and 90.2% with pegaspargase (P = .78). The 4-year overall survival rate was 94.8% and 95.6%, respectively (P = .74).

In closing, Dr. Vrooman said these data suggest SC-PEG provides similar results as standard pegaspargase. She noted that these data informed the U.S. approval of SC-PEG for pediatric and young adult ALL.

This trial was sponsored by the Dana-Farber Cancer Institute in collaboration with Shire and the National Cancer Institute. Dr. Vrooman said she had no relationships to disclose.

[email protected]

SOURCE: Vrooman LM et al. ASCO 2019. Abstract 10006.

CHICAGO – A low intensity chemotherapy regimen may be the best approach to bridge patients waiting for chimeric antigen receptor (CAR) T-cell therapy, according to a retrospective analysis of adults with acute lymphoblastic leukemia (ALL).

Investigators found that high intensity bridging regimens provided no clear outcome benefit, but did produce a greater number of infections.

But the decision on the type of regimen is very much dependent on the individual patient, Karlo Perica, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said at the annual meeting of the American Society of Clinical Oncology.

Mary Ellen Schneider/MDedge News

Dr. Perica and his colleagues at Memorial Sloan Kettering examined the effectiveness and toxicity of bridging therapies provided to relapsed or refractory ALL patients waiting to receive CD19 CAR T-cell therapy as part of a phase 1 trial (N Engl J Med. 2018 Feb 1;378[5]:449-59).

Bridging therapy was defined as any therapy given from leukapheresis to cell infusion.

The low-intensity regimens included POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone, or combinations), liposomal vincristine, mini-hyper CVD (reduced cyclophosphamide, dexamethasone, methotrexate, Ara-C), blinatumomab, inotuzumab, oral tyrosine kinase inhibitor-based regimens, or hydroxyurea.

The high-intensity regimens included hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone), high-dose cytarabine, attenuated FLAG/FLAG-IDA (reduced fludarabine, cytarabine, G-CSF plus or minus idarubicin), and pediatric-type induction.

Of the 53 patients who were ultimately infused with CAR T cells, 19 received some type of high intensity regimen, 29 received low intensity regimens, and 5 received no bridging treatment. The group overall was heavily pretreated. Nearly a third of the low intensity and no bridging patients and 42% of the high intensity patients had previously undergone transplant. More than 40% of the low intensity and no bridging patients and about a quarter of the high intensity bridging group had four or more prior lines of therapy.

The use of high intensity bridging therapy was not associated with improved overall response or relapse-free survival to CAR T-cell therapy, the investigators reported. In a subgroup with 23 high disease burden patients with greater than 20% blasts, there was no difference in MRD-negative complete response by intensity (75% versus 60%, Fisher’s P = .65).

High intensity bridging was also not associated with successful CAR T-cell infusion, versus low intensity regimens (63% versus 79%, P greater than .05) or a combined endpoint of CAR T-cell infusion plus transplant or alternative treatment (80% versus 86%, P greater than .05).

In terms of toxicity, the high intensity bridging regimens were associated with a higher rate of grade 3 or 4 infections – 15 versus 11 infections (Fisher’s P = .002). But there was no association with post-infusion grade 3 or 4 cytokine release syndrome or neurotoxicity.

Dr. Perica said the results reflect that the real goal of bridging is not to reduce disease burden but instead to successfully bring patients to the next phase of their treatment. “The goal of the bridging therapy is to get the patient to the CAR infusion,” he said.

Due to the retrospective nature of the study, Dr. Perica said he can’t recommend any single bridging regimen and he emphasized that the decisions are patient-specific.

The original study was funded by several foundations and Juno Therapeutics. Dr. Perica reported royalties from technology licensed to Neximmune.

[email protected]

SOURCE: Perica K et al. ASCO 2019, Abstract 2520.

CHICAGO – A low intensity chemotherapy regimen may be the best approach to bridge patients waiting for chimeric antigen receptor (CAR) T-cell therapy, according to a retrospective analysis of adults with acute lymphoblastic leukemia (ALL).

Investigators found that high intensity bridging regimens provided no clear outcome benefit, but did produce a greater number of infections.

But the decision on the type of regimen is very much dependent on the individual patient, Karlo Perica, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said at the annual meeting of the American Society of Clinical Oncology.

Mary Ellen Schneider/MDedge News

Dr. Perica and his colleagues at Memorial Sloan Kettering examined the effectiveness and toxicity of bridging therapies provided to relapsed or refractory ALL patients waiting to receive CD19 CAR T-cell therapy as part of a phase 1 trial (N Engl J Med. 2018 Feb 1;378[5]:449-59).

Bridging therapy was defined as any therapy given from leukapheresis to cell infusion.

The low-intensity regimens included POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone, or combinations), liposomal vincristine, mini-hyper CVD (reduced cyclophosphamide, dexamethasone, methotrexate, Ara-C), blinatumomab, inotuzumab, oral tyrosine kinase inhibitor-based regimens, or hydroxyurea.

The high-intensity regimens included hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone), high-dose cytarabine, attenuated FLAG/FLAG-IDA (reduced fludarabine, cytarabine, G-CSF plus or minus idarubicin), and pediatric-type induction.

Of the 53 patients who were ultimately infused with CAR T cells, 19 received some type of high intensity regimen, 29 received low intensity regimens, and 5 received no bridging treatment. The group overall was heavily pretreated. Nearly a third of the low intensity and no bridging patients and 42% of the high intensity patients had previously undergone transplant. More than 40% of the low intensity and no bridging patients and about a quarter of the high intensity bridging group had four or more prior lines of therapy.

The use of high intensity bridging therapy was not associated with improved overall response or relapse-free survival to CAR T-cell therapy, the investigators reported. In a subgroup with 23 high disease burden patients with greater than 20% blasts, there was no difference in MRD-negative complete response by intensity (75% versus 60%, Fisher’s P = .65).

High intensity bridging was also not associated with successful CAR T-cell infusion, versus low intensity regimens (63% versus 79%, P greater than .05) or a combined endpoint of CAR T-cell infusion plus transplant or alternative treatment (80% versus 86%, P greater than .05).

In terms of toxicity, the high intensity bridging regimens were associated with a higher rate of grade 3 or 4 infections – 15 versus 11 infections (Fisher’s P = .002). But there was no association with post-infusion grade 3 or 4 cytokine release syndrome or neurotoxicity.

Dr. Perica said the results reflect that the real goal of bridging is not to reduce disease burden but instead to successfully bring patients to the next phase of their treatment. “The goal of the bridging therapy is to get the patient to the CAR infusion,” he said.

Due to the retrospective nature of the study, Dr. Perica said he can’t recommend any single bridging regimen and he emphasized that the decisions are patient-specific.

The original study was funded by several foundations and Juno Therapeutics. Dr. Perica reported royalties from technology licensed to Neximmune.

[email protected]

SOURCE: Perica K et al. ASCO 2019, Abstract 2520.

CHICAGO – A low intensity chemotherapy regimen may be the best approach to bridge patients waiting for chimeric antigen receptor (CAR) T-cell therapy, according to a retrospective analysis of adults with acute lymphoblastic leukemia (ALL).

Investigators found that high intensity bridging regimens provided no clear outcome benefit, but did produce a greater number of infections.

But the decision on the type of regimen is very much dependent on the individual patient, Karlo Perica, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said at the annual meeting of the American Society of Clinical Oncology.

Mary Ellen Schneider/MDedge News

Dr. Perica and his colleagues at Memorial Sloan Kettering examined the effectiveness and toxicity of bridging therapies provided to relapsed or refractory ALL patients waiting to receive CD19 CAR T-cell therapy as part of a phase 1 trial (N Engl J Med. 2018 Feb 1;378[5]:449-59).

Bridging therapy was defined as any therapy given from leukapheresis to cell infusion.

The low-intensity regimens included POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone, or combinations), liposomal vincristine, mini-hyper CVD (reduced cyclophosphamide, dexamethasone, methotrexate, Ara-C), blinatumomab, inotuzumab, oral tyrosine kinase inhibitor-based regimens, or hydroxyurea.

The high-intensity regimens included hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone), high-dose cytarabine, attenuated FLAG/FLAG-IDA (reduced fludarabine, cytarabine, G-CSF plus or minus idarubicin), and pediatric-type induction.

Of the 53 patients who were ultimately infused with CAR T cells, 19 received some type of high intensity regimen, 29 received low intensity regimens, and 5 received no bridging treatment. The group overall was heavily pretreated. Nearly a third of the low intensity and no bridging patients and 42% of the high intensity patients had previously undergone transplant. More than 40% of the low intensity and no bridging patients and about a quarter of the high intensity bridging group had four or more prior lines of therapy.

The use of high intensity bridging therapy was not associated with improved overall response or relapse-free survival to CAR T-cell therapy, the investigators reported. In a subgroup with 23 high disease burden patients with greater than 20% blasts, there was no difference in MRD-negative complete response by intensity (75% versus 60%, Fisher’s P = .65).

High intensity bridging was also not associated with successful CAR T-cell infusion, versus low intensity regimens (63% versus 79%, P greater than .05) or a combined endpoint of CAR T-cell infusion plus transplant or alternative treatment (80% versus 86%, P greater than .05).

In terms of toxicity, the high intensity bridging regimens were associated with a higher rate of grade 3 or 4 infections – 15 versus 11 infections (Fisher’s P = .002). But there was no association with post-infusion grade 3 or 4 cytokine release syndrome or neurotoxicity.

Dr. Perica said the results reflect that the real goal of bridging is not to reduce disease burden but instead to successfully bring patients to the next phase of their treatment. “The goal of the bridging therapy is to get the patient to the CAR infusion,” he said.

Due to the retrospective nature of the study, Dr. Perica said he can’t recommend any single bridging regimen and he emphasized that the decisions are patient-specific.

The original study was funded by several foundations and Juno Therapeutics. Dr. Perica reported royalties from technology licensed to Neximmune.

[email protected]

SOURCE: Perica K et al. ASCO 2019, Abstract 2520.

CHICAGO – Administering CPX-351 prior to a three-drug regimen produced a high response rate in pediatric patients with acute myeloid leukemia (AML) in first relapse.

Jennifer Smith/MDedge News

In a phase 1/2 trial, CPX-351 followed by fludarabine, cytarabine, and filgrastim (FLAG) produced an overall response rate of 81%, and 70% of responders had their best response while receiving CPX-351.

“This is the best response rate published in North America for those [pediatric AML patients] in first relapse,” said Todd Cooper, DO, of Seattle Children’s Hospital in Washington.

Dr. Cooper presented results from the phase 1/2 AAML1421 trial (NCT02642965) at the annual meeting of the American Society of Clinical Oncology.

The primary objective of phase 1 was to determine the recommended phase 2 dose and toxicities of CPX-351, a liposomal preparation of cytarabine and daunorubicin. The primary objective of phase 2 was to assess the best response in patients who received CPX-351 in cycle 1 and FLAG in cycle 2.

The trial enrolled 38 AML patients, 6 in the dose-finding phase and 32 in the efficacy phase. The patients’ median age at study entry was 11.91 years (range, 1.81-21.5). Most patients (88.9%) had CNS 1 disease, and most (73.7%) had not received a transplant.

Half of patients had a first complete response (CR) that lasted 180 to 365 days, 13.2% had a first CR lasting less than 180 days, and 36.8% had a first CR lasting more than 1 year.

Dosing and toxicity

During the dose-finding portion of the study, the first dose level of CPX-351 was 135 units/m² on days 1, 3, and 5. There was one dose-limiting toxicity — grade 3 decrease in ejection fraction — so 135 units/m² was deemed the recommended phase 2 dose.

The most common grade 3 or higher adverse events observed with CPX-351 in cycle 1 were infections and infestations (47.4%), febrile neutropenia (44.7%), maculopapular rash (39.5%), and prolonged QT interval (18.4%).

The most common grade 3 or higher adverse events observed with FLAG in cycle 2 were febrile neutropenia (23.1%), prolonged QT interval (23.1%), and infections and infestations (19.2%).

Response and survival

There were 37 patients evaluable for response. The overall response rate was defined as CR plus CR without platelet recovery (CRp) plus CR with incomplete hematologic recovery (CRi).

The overall response rate was 81.1% (n = 30), which included 20 CRs (54.1%), 5 CRps (13.5%), and 5 CRis (13.5%). Five patients had a partial response (13.5%), and two patients had treatment failure (5.4%).

During CPX-351 treatment (n = 37), the CR rate was 37.8% (n = 14), the CRp rate was 5.4% (n = 2), and the CRi rate was 32.4% (n = 12).

During FLAG treatment (n = 27), the CR rate was 48.1% (n = 13), the CRp rate was 25.9% (n = 7), and the CRi rate was 7.4% (n = 2).

Of the 25 patients who achieved a CR or CRp at any time, 21 (84%) were minimal residual disease negative by flow cytometry. Twelve patients were minimal residual disease negative after cycle 1.

Most patients who achieved a CRi or better (83.3%) went on to hematopoietic stem cell transplant.

The 2-year overall survival was 47% for all patients and 60% for responders. None of the non-responders were still alive 2 years after therapy.

“The results certainly warrant a phase 3 study of CPX-351,” Dr. Cooper said. “In fact, it is the lead molecule that’s going to be incorporated into the next COG phase 3 study.”

AAML1421 was sponsored by the Children’s Oncology Group in collaboration with the National Cancer Institute. Dr. Cooper disclosed relationships with Juno Therapeutics and Celgene.

[email protected]

SOURCE: Cooper TM et al. ASCO 2019. Abstract 10003.

CHICAGO – Administering CPX-351 prior to a three-drug regimen produced a high response rate in pediatric patients with acute myeloid leukemia (AML) in first relapse.

Jennifer Smith/MDedge News

In a phase 1/2 trial, CPX-351 followed by fludarabine, cytarabine, and filgrastim (FLAG) produced an overall response rate of 81%, and 70% of responders had their best response while receiving CPX-351.

“This is the best response rate published in North America for those [pediatric AML patients] in first relapse,” said Todd Cooper, DO, of Seattle Children’s Hospital in Washington.

Dr. Cooper presented results from the phase 1/2 AAML1421 trial (NCT02642965) at the annual meeting of the American Society of Clinical Oncology.

The primary objective of phase 1 was to determine the recommended phase 2 dose and toxicities of CPX-351, a liposomal preparation of cytarabine and daunorubicin. The primary objective of phase 2 was to assess the best response in patients who received CPX-351 in cycle 1 and FLAG in cycle 2.

The trial enrolled 38 AML patients, 6 in the dose-finding phase and 32 in the efficacy phase. The patients’ median age at study entry was 11.91 years (range, 1.81-21.5). Most patients (88.9%) had CNS 1 disease, and most (73.7%) had not received a transplant.

Half of patients had a first complete response (CR) that lasted 180 to 365 days, 13.2% had a first CR lasting less than 180 days, and 36.8% had a first CR lasting more than 1 year.

Dosing and toxicity

During the dose-finding portion of the study, the first dose level of CPX-351 was 135 units/m² on days 1, 3, and 5. There was one dose-limiting toxicity — grade 3 decrease in ejection fraction — so 135 units/m² was deemed the recommended phase 2 dose.

The most common grade 3 or higher adverse events observed with CPX-351 in cycle 1 were infections and infestations (47.4%), febrile neutropenia (44.7%), maculopapular rash (39.5%), and prolonged QT interval (18.4%).

The most common grade 3 or higher adverse events observed with FLAG in cycle 2 were febrile neutropenia (23.1%), prolonged QT interval (23.1%), and infections and infestations (19.2%).

Response and survival

There were 37 patients evaluable for response. The overall response rate was defined as CR plus CR without platelet recovery (CRp) plus CR with incomplete hematologic recovery (CRi).

The overall response rate was 81.1% (n = 30), which included 20 CRs (54.1%), 5 CRps (13.5%), and 5 CRis (13.5%). Five patients had a partial response (13.5%), and two patients had treatment failure (5.4%).

During CPX-351 treatment (n = 37), the CR rate was 37.8% (n = 14), the CRp rate was 5.4% (n = 2), and the CRi rate was 32.4% (n = 12).

During FLAG treatment (n = 27), the CR rate was 48.1% (n = 13), the CRp rate was 25.9% (n = 7), and the CRi rate was 7.4% (n = 2).

Of the 25 patients who achieved a CR or CRp at any time, 21 (84%) were minimal residual disease negative by flow cytometry. Twelve patients were minimal residual disease negative after cycle 1.

Most patients who achieved a CRi or better (83.3%) went on to hematopoietic stem cell transplant.

The 2-year overall survival was 47% for all patients and 60% for responders. None of the non-responders were still alive 2 years after therapy.

“The results certainly warrant a phase 3 study of CPX-351,” Dr. Cooper said. “In fact, it is the lead molecule that’s going to be incorporated into the next COG phase 3 study.”

AAML1421 was sponsored by the Children’s Oncology Group in collaboration with the National Cancer Institute. Dr. Cooper disclosed relationships with Juno Therapeutics and Celgene.

[email protected]

SOURCE: Cooper TM et al. ASCO 2019. Abstract 10003.

CHICAGO – Administering CPX-351 prior to a three-drug regimen produced a high response rate in pediatric patients with acute myeloid leukemia (AML) in first relapse.

Jennifer Smith/MDedge News

In a phase 1/2 trial, CPX-351 followed by fludarabine, cytarabine, and filgrastim (FLAG) produced an overall response rate of 81%, and 70% of responders had their best response while receiving CPX-351.

“This is the best response rate published in North America for those [pediatric AML patients] in first relapse,” said Todd Cooper, DO, of Seattle Children’s Hospital in Washington.

Dr. Cooper presented results from the phase 1/2 AAML1421 trial (NCT02642965) at the annual meeting of the American Society of Clinical Oncology.

The primary objective of phase 1 was to determine the recommended phase 2 dose and toxicities of CPX-351, a liposomal preparation of cytarabine and daunorubicin. The primary objective of phase 2 was to assess the best response in patients who received CPX-351 in cycle 1 and FLAG in cycle 2.

The trial enrolled 38 AML patients, 6 in the dose-finding phase and 32 in the efficacy phase. The patients’ median age at study entry was 11.91 years (range, 1.81-21.5). Most patients (88.9%) had CNS 1 disease, and most (73.7%) had not received a transplant.

Half of patients had a first complete response (CR) that lasted 180 to 365 days, 13.2% had a first CR lasting less than 180 days, and 36.8% had a first CR lasting more than 1 year.

Dosing and toxicity

During the dose-finding portion of the study, the first dose level of CPX-351 was 135 units/m² on days 1, 3, and 5. There was one dose-limiting toxicity — grade 3 decrease in ejection fraction — so 135 units/m² was deemed the recommended phase 2 dose.

The most common grade 3 or higher adverse events observed with CPX-351 in cycle 1 were infections and infestations (47.4%), febrile neutropenia (44.7%), maculopapular rash (39.5%), and prolonged QT interval (18.4%).

The most common grade 3 or higher adverse events observed with FLAG in cycle 2 were febrile neutropenia (23.1%), prolonged QT interval (23.1%), and infections and infestations (19.2%).

Response and survival

There were 37 patients evaluable for response. The overall response rate was defined as CR plus CR without platelet recovery (CRp) plus CR with incomplete hematologic recovery (CRi).

The overall response rate was 81.1% (n = 30), which included 20 CRs (54.1%), 5 CRps (13.5%), and 5 CRis (13.5%). Five patients had a partial response (13.5%), and two patients had treatment failure (5.4%).

During CPX-351 treatment (n = 37), the CR rate was 37.8% (n = 14), the CRp rate was 5.4% (n = 2), and the CRi rate was 32.4% (n = 12).

During FLAG treatment (n = 27), the CR rate was 48.1% (n = 13), the CRp rate was 25.9% (n = 7), and the CRi rate was 7.4% (n = 2).

Of the 25 patients who achieved a CR or CRp at any time, 21 (84%) were minimal residual disease negative by flow cytometry. Twelve patients were minimal residual disease negative after cycle 1.

Most patients who achieved a CRi or better (83.3%) went on to hematopoietic stem cell transplant.

The 2-year overall survival was 47% for all patients and 60% for responders. None of the non-responders were still alive 2 years after therapy.

“The results certainly warrant a phase 3 study of CPX-351,” Dr. Cooper said. “In fact, it is the lead molecule that’s going to be incorporated into the next COG phase 3 study.”

AAML1421 was sponsored by the Children’s Oncology Group in collaboration with the National Cancer Institute. Dr. Cooper disclosed relationships with Juno Therapeutics and Celgene.

[email protected]

SOURCE: Cooper TM et al. ASCO 2019. Abstract 10003.

A combination of venetoclax and ibrutinib may be a safe and effective treatment option for previously untreated elderly and high-risk patients with chronic lymphocytic leukemia (CLL), according to investigators of a phase 2 trial of the combination.

VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

About 88% of patients achieved complete remission or complete remission with incomplete count recovery after 12 cycles of treatment, reported lead author Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

There were no new safety signals for the combination of ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, and venetoclax, a B-cell lymphoma 2 protein inhibitor, the investigators noted.

“This combination was reported to be safe and active in patients with mantle cell lymphoma,” they wrote in the New England Journal of Medicine. “Given the clinically complementary activity, preclinical synergism, and nonoverlapping toxic effects, we examined the safety and efficacy of combined ibrutinib and venetoclax treatment in previously untreated patients with CLL.”

In particular, the investigators recruited older patients, as this is a common population that can be challenging to treat. “Because CLL typically occurs in older adults, the majority of patients who need treatment are older than 65 years of age,” the investigators wrote. “This group of patients often has unacceptable side effects and has a lower rate of complete remission and undetectable minimal residual disease with chemoimmunotherapy than younger patients.”

The open-label, phase 2 trial enrolled 80 elderly and high-risk patients with previously untreated CLL. Eligibility required an age of at least 65 years or presence of at least one high-risk genetic feature; namely, mutated TP53, unmutated IgVH, or chromosome 11q deletion.

In order to reduce the risk of tumor lysis syndrome, ibrutinib (420 mg once daily) was given as monotherapy for three 28-day cycles. From the fourth cycle onward, venetoclax was also given, with weekly dose escalations to a target dose of 400 mg once daily. The combination was given for 24 cycles, with treatment continuation offered to patients who were still positive for minimal residual disease.

The median patient age was 65 years, with 30% of the population aged 70 years or older. A large majority (92%) had at least one high-risk genetic feature.

Following initiation with three cycles of ibrutinib, most patients had partial responses, the investigators wrote; however, with the addition of venetoclax, responses improved over time. Of all 80 patients, 59 (74%) had a best response of complete remission or complete remission with incomplete count recovery.

After six cycles, 51 out of 70 patients (73%) achieved this marker. After 12 cycles, 29 of 33 patients (88%) had this response, with 61% of the same group demonstrating undetectable minimal residual disease in bone marrow.

After 18 cycles, 25 of 26 patients (96%) had complete remission or complete remission with incomplete count recovery, 18 of which (69%) were negative for minimal residual disease. Three patients completed 24 cycles of combined therapy, all of whom achieved complete remission or complete remission with incomplete count recovery and undetectable minimal residual disease.

Focusing on patients aged 65 years or older, 74% had complete remission or complete remission with incomplete count recovery after six cycles of therapy and nearly half (44%) had undetectable minimal residual disease. After 12 cycles, these rates increased to 94% and 76%, respectively. Responses were also seen across genetically high-risk subgroups.

One patient died from a cryptococcal infection of the central nervous system; this was deemed unrelated to treatment, as symptoms began prior to initiation of treatment and only one dose of ibrutinib was given.

The estimated 1-year progression-free survival rate was 98% and the estimated overall survival rate was 99%. At the time of publication, no patients had disease progression.

Among all patients, 60% experienced grade 3 or higher adverse events, the most common being neutropenia (48%).

Almost half of the patient population (44%) required dose reductions of ibrutinib, most commonly because of atrial fibrillation, and 24% required dose reductions of venetoclax, most often because of neutropenia.

“Our data showed that combination therapy with ibrutinib and venetoclax was effective in patients with CLL, with no new toxic effects from the combination that were not reported previously for the individual agents,” the investigators wrote, adding that the efficacy findings were also “substantially better” than what has been reported with monotherapy for each of the agents in patients with CLL.

The study was funded by AbbVie, the University of Texas MD Anderson Cancer Center Chronic Lymphocytic Leukemia Moon Shot program, the Andrew Sabin Family Foundation, and the CLL Global Research Foundation. The investigators reported relationships with AbbVie, Incyte, Celgene, and other companies.

SOURCE: Jain N et al. N Engl J Med. 2019;380:2095-103.

A combination of venetoclax and ibrutinib may be a safe and effective treatment option for previously untreated elderly and high-risk patients with chronic lymphocytic leukemia (CLL), according to investigators of a phase 2 trial of the combination.

VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

About 88% of patients achieved complete remission or complete remission with incomplete count recovery after 12 cycles of treatment, reported lead author Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

There were no new safety signals for the combination of ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, and venetoclax, a B-cell lymphoma 2 protein inhibitor, the investigators noted.

“This combination was reported to be safe and active in patients with mantle cell lymphoma,” they wrote in the New England Journal of Medicine. “Given the clinically complementary activity, preclinical synergism, and nonoverlapping toxic effects, we examined the safety and efficacy of combined ibrutinib and venetoclax treatment in previously untreated patients with CLL.”

In particular, the investigators recruited older patients, as this is a common population that can be challenging to treat. “Because CLL typically occurs in older adults, the majority of patients who need treatment are older than 65 years of age,” the investigators wrote. “This group of patients often has unacceptable side effects and has a lower rate of complete remission and undetectable minimal residual disease with chemoimmunotherapy than younger patients.”

The open-label, phase 2 trial enrolled 80 elderly and high-risk patients with previously untreated CLL. Eligibility required an age of at least 65 years or presence of at least one high-risk genetic feature; namely, mutated TP53, unmutated IgVH, or chromosome 11q deletion.

In order to reduce the risk of tumor lysis syndrome, ibrutinib (420 mg once daily) was given as monotherapy for three 28-day cycles. From the fourth cycle onward, venetoclax was also given, with weekly dose escalations to a target dose of 400 mg once daily. The combination was given for 24 cycles, with treatment continuation offered to patients who were still positive for minimal residual disease.

The median patient age was 65 years, with 30% of the population aged 70 years or older. A large majority (92%) had at least one high-risk genetic feature.

Following initiation with three cycles of ibrutinib, most patients had partial responses, the investigators wrote; however, with the addition of venetoclax, responses improved over time. Of all 80 patients, 59 (74%) had a best response of complete remission or complete remission with incomplete count recovery.

After six cycles, 51 out of 70 patients (73%) achieved this marker. After 12 cycles, 29 of 33 patients (88%) had this response, with 61% of the same group demonstrating undetectable minimal residual disease in bone marrow.

After 18 cycles, 25 of 26 patients (96%) had complete remission or complete remission with incomplete count recovery, 18 of which (69%) were negative for minimal residual disease. Three patients completed 24 cycles of combined therapy, all of whom achieved complete remission or complete remission with incomplete count recovery and undetectable minimal residual disease.

Focusing on patients aged 65 years or older, 74% had complete remission or complete remission with incomplete count recovery after six cycles of therapy and nearly half (44%) had undetectable minimal residual disease. After 12 cycles, these rates increased to 94% and 76%, respectively. Responses were also seen across genetically high-risk subgroups.

One patient died from a cryptococcal infection of the central nervous system; this was deemed unrelated to treatment, as symptoms began prior to initiation of treatment and only one dose of ibrutinib was given.

The estimated 1-year progression-free survival rate was 98% and the estimated overall survival rate was 99%. At the time of publication, no patients had disease progression.

Among all patients, 60% experienced grade 3 or higher adverse events, the most common being neutropenia (48%).

Almost half of the patient population (44%) required dose reductions of ibrutinib, most commonly because of atrial fibrillation, and 24% required dose reductions of venetoclax, most often because of neutropenia.

“Our data showed that combination therapy with ibrutinib and venetoclax was effective in patients with CLL, with no new toxic effects from the combination that were not reported previously for the individual agents,” the investigators wrote, adding that the efficacy findings were also “substantially better” than what has been reported with monotherapy for each of the agents in patients with CLL.

The study was funded by AbbVie, the University of Texas MD Anderson Cancer Center Chronic Lymphocytic Leukemia Moon Shot program, the Andrew Sabin Family Foundation, and the CLL Global Research Foundation. The investigators reported relationships with AbbVie, Incyte, Celgene, and other companies.

SOURCE: Jain N et al. N Engl J Med. 2019;380:2095-103.

A combination of venetoclax and ibrutinib may be a safe and effective treatment option for previously untreated elderly and high-risk patients with chronic lymphocytic leukemia (CLL), according to investigators of a phase 2 trial of the combination.

VashiDonsk/Wikimedia Commons/Creative Commons BY-SA 3.0

About 88% of patients achieved complete remission or complete remission with incomplete count recovery after 12 cycles of treatment, reported lead author Nitin Jain, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues.

There were no new safety signals for the combination of ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase, and venetoclax, a B-cell lymphoma 2 protein inhibitor, the investigators noted.

“This combination was reported to be safe and active in patients with mantle cell lymphoma,” they wrote in the New England Journal of Medicine. “Given the clinically complementary activity, preclinical synergism, and nonoverlapping toxic effects, we examined the safety and efficacy of combined ibrutinib and venetoclax treatment in previously untreated patients with CLL.”

In particular, the investigators recruited older patients, as this is a common population that can be challenging to treat. “Because CLL typically occurs in older adults, the majority of patients who need treatment are older than 65 years of age,” the investigators wrote. “This group of patients often has unacceptable side effects and has a lower rate of complete remission and undetectable minimal residual disease with chemoimmunotherapy than younger patients.”

The open-label, phase 2 trial enrolled 80 elderly and high-risk patients with previously untreated CLL. Eligibility required an age of at least 65 years or presence of at least one high-risk genetic feature; namely, mutated TP53, unmutated IgVH, or chromosome 11q deletion.

In order to reduce the risk of tumor lysis syndrome, ibrutinib (420 mg once daily) was given as monotherapy for three 28-day cycles. From the fourth cycle onward, venetoclax was also given, with weekly dose escalations to a target dose of 400 mg once daily. The combination was given for 24 cycles, with treatment continuation offered to patients who were still positive for minimal residual disease.

The median patient age was 65 years, with 30% of the population aged 70 years or older. A large majority (92%) had at least one high-risk genetic feature.

Following initiation with three cycles of ibrutinib, most patients had partial responses, the investigators wrote; however, with the addition of venetoclax, responses improved over time. Of all 80 patients, 59 (74%) had a best response of complete remission or complete remission with incomplete count recovery.

After six cycles, 51 out of 70 patients (73%) achieved this marker. After 12 cycles, 29 of 33 patients (88%) had this response, with 61% of the same group demonstrating undetectable minimal residual disease in bone marrow.

After 18 cycles, 25 of 26 patients (96%) had complete remission or complete remission with incomplete count recovery, 18 of which (69%) were negative for minimal residual disease. Three patients completed 24 cycles of combined therapy, all of whom achieved complete remission or complete remission with incomplete count recovery and undetectable minimal residual disease.

Focusing on patients aged 65 years or older, 74% had complete remission or complete remission with incomplete count recovery after six cycles of therapy and nearly half (44%) had undetectable minimal residual disease. After 12 cycles, these rates increased to 94% and 76%, respectively. Responses were also seen across genetically high-risk subgroups.

One patient died from a cryptococcal infection of the central nervous system; this was deemed unrelated to treatment, as symptoms began prior to initiation of treatment and only one dose of ibrutinib was given.

The estimated 1-year progression-free survival rate was 98% and the estimated overall survival rate was 99%. At the time of publication, no patients had disease progression.

Among all patients, 60% experienced grade 3 or higher adverse events, the most common being neutropenia (48%).

Almost half of the patient population (44%) required dose reductions of ibrutinib, most commonly because of atrial fibrillation, and 24% required dose reductions of venetoclax, most often because of neutropenia.

“Our data showed that combination therapy with ibrutinib and venetoclax was effective in patients with CLL, with no new toxic effects from the combination that were not reported previously for the individual agents,” the investigators wrote, adding that the efficacy findings were also “substantially better” than what has been reported with monotherapy for each of the agents in patients with CLL.

The study was funded by AbbVie, the University of Texas MD Anderson Cancer Center Chronic Lymphocytic Leukemia Moon Shot program, the Andrew Sabin Family Foundation, and the CLL Global Research Foundation. The investigators reported relationships with AbbVie, Incyte, Celgene, and other companies.

SOURCE: Jain N et al. N Engl J Med. 2019;380:2095-103.

A genetic analysis of patients with chronic lymphocytic leukemia treated with frontline, rituximab-based regimens found that deletion 11q22 and unmutated IgVH status may predict worse prognosis.

Michaela Spunarova, MD, of Masaryk University, Brno, Czech Republic, and colleagues conducted a genetic analysis of 177 patients with chronic lymphocytic leukemia (CLL). The results of the analysis were published in Leukemia Research.

The study focused on patients with CLL with an intact TP53 gene, looking at recurrently muted genes in CLL, genomic aberrations by fluorescence in situ hybridization, and IgVH status, according to the researchers.

The team analyzed the effects of these mutations on progression-free survival (PFS) following frontline treatment with bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) therapeutic regimens.

Dr. Spunarova and colleagues used next-generation sequencing to analyze DNA from the patient samples. Data on 11q22, 13q14, trisomy 12, and IgVH mutation status were also considered in the analyses of PFS.

After analysis, the researchers validated that unmutated IgVH status is an indicator of poor prognosis in CLL patients with wild-type TP53 treated with frontline FCR.

When looking at both BR and FCR regimens, a single 11q22 deletion, lacking an ATM mutation on the other allele, resulted in the shortest PFS, at a median of just 16 months.

“Based on our data, special attention should be given to CLL patients harboring a sole 11q22 deletion, with no ATM mutation on the other allele, who manifest particularly short PFS,” they noted.

The researchers acknowledged a key limitation of the study was the small sample size. As a result, the results should be interpreted in a careful manner.

The study was funded by the Ministry of Health of the Czech Republic. The authors reported having no conflicts of interest.

SOURCE: Spunarova M et al. Leuk Res. 2019 Jun;81:75-81.

A genetic analysis of patients with chronic lymphocytic leukemia treated with frontline, rituximab-based regimens found that deletion 11q22 and unmutated IgVH status may predict worse prognosis.

Michaela Spunarova, MD, of Masaryk University, Brno, Czech Republic, and colleagues conducted a genetic analysis of 177 patients with chronic lymphocytic leukemia (CLL). The results of the analysis were published in Leukemia Research.

The study focused on patients with CLL with an intact TP53 gene, looking at recurrently muted genes in CLL, genomic aberrations by fluorescence in situ hybridization, and IgVH status, according to the researchers.

The team analyzed the effects of these mutations on progression-free survival (PFS) following frontline treatment with bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) therapeutic regimens.

Dr. Spunarova and colleagues used next-generation sequencing to analyze DNA from the patient samples. Data on 11q22, 13q14, trisomy 12, and IgVH mutation status were also considered in the analyses of PFS.

After analysis, the researchers validated that unmutated IgVH status is an indicator of poor prognosis in CLL patients with wild-type TP53 treated with frontline FCR.

When looking at both BR and FCR regimens, a single 11q22 deletion, lacking an ATM mutation on the other allele, resulted in the shortest PFS, at a median of just 16 months.

“Based on our data, special attention should be given to CLL patients harboring a sole 11q22 deletion, with no ATM mutation on the other allele, who manifest particularly short PFS,” they noted.

The researchers acknowledged a key limitation of the study was the small sample size. As a result, the results should be interpreted in a careful manner.

The study was funded by the Ministry of Health of the Czech Republic. The authors reported having no conflicts of interest.

SOURCE: Spunarova M et al. Leuk Res. 2019 Jun;81:75-81.

A genetic analysis of patients with chronic lymphocytic leukemia treated with frontline, rituximab-based regimens found that deletion 11q22 and unmutated IgVH status may predict worse prognosis.

Michaela Spunarova, MD, of Masaryk University, Brno, Czech Republic, and colleagues conducted a genetic analysis of 177 patients with chronic lymphocytic leukemia (CLL). The results of the analysis were published in Leukemia Research.

The study focused on patients with CLL with an intact TP53 gene, looking at recurrently muted genes in CLL, genomic aberrations by fluorescence in situ hybridization, and IgVH status, according to the researchers.

The team analyzed the effects of these mutations on progression-free survival (PFS) following frontline treatment with bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) therapeutic regimens.

Dr. Spunarova and colleagues used next-generation sequencing to analyze DNA from the patient samples. Data on 11q22, 13q14, trisomy 12, and IgVH mutation status were also considered in the analyses of PFS.

After analysis, the researchers validated that unmutated IgVH status is an indicator of poor prognosis in CLL patients with wild-type TP53 treated with frontline FCR.

When looking at both BR and FCR regimens, a single 11q22 deletion, lacking an ATM mutation on the other allele, resulted in the shortest PFS, at a median of just 16 months.

“Based on our data, special attention should be given to CLL patients harboring a sole 11q22 deletion, with no ATM mutation on the other allele, who manifest particularly short PFS,” they noted.

The researchers acknowledged a key limitation of the study was the small sample size. As a result, the results should be interpreted in a careful manner.

The study was funded by the Ministry of Health of the Czech Republic. The authors reported having no conflicts of interest.

SOURCE: Spunarova M et al. Leuk Res. 2019 Jun;81:75-81.

NEW ORLEANS – Next-generation sequencing of peripheral blood is at least as effective as flow cytometry of bone marrow for assessing minimal residual disease, according to a new study.

Researchers compared bone marrow flow cytometry (FC) and peripheral blood next-generation sequencing (NGS) for minimal residual disease (MRD) assessment in pediatric and young adult patients with B-cell acute lymphoblastic leukemia (B-ALL) who received treatment with tisagenlecleucel. There was a high level of concordance between the assays, but the NGS assay detected more MRD-positive samples and NGS results provided a longer lead time to relapse.

Michael A. Pulsipher, MD, of the Children’s Hospital Los Angeles, presented these results at the annual meeting of the American Society of Pediatric Hematology/Oncology.

The researchers analyzed samples from pediatric and young adult patients aged 2-25 years who had relapsed or refractory B-ALL and received treatment with tisagenlecleucel on the ELIANA or ENSIGN trials.

The patients had received at least two prior lines of therapy and were ineligible for allogeneic transplant. They received a single dose of tisagenlecleucel. MRD was assessed before tisagenlecleucel infusion, at various time points after infusion, and at relapse.

Dr. Pulsipher and his colleagues compared MRD results from an NGS assay – Adaptive Biotechnologies’ clonoSEQ – using peripheral blood and results from FC of bone marrow. NGS and FC results were available for 237 samples from 83 patients.

After treatment, NGS detected more MRD-positive samples at each sensitivity level tested (10^-4, 10^-5, and 10^-6). At 10^-6, NGS detected 18% more MRD-positive samples than did FC – 50% and 32%, respectively.

Detection of MRD positivity prior to relapse was faster with NGS than with FC. In 17 of 34 patients with morphological relapse, NGS provided a median lead time of 67 days. FC provided a median lead time of 39 days in 11 of the 34 patients.

About 80% of patients who had an MRD status of zero by NGS at day 28 remained relapse-free for up to 3 years.

Among complete responders (n = 50), the duration of response was significantly longer in patients who had an MRD status of zero at day 28 by NGS than in patients who had an MRD status greater than zero (P = .0003). Overall survival was significantly better among patients with an MRD status of zero as well (P = .0004).

Dr. Pulsipher said additional studies are needed to confirm these findings and determine the best way to know if a patient has been cured or needs additional therapy after tisagenlecleucel.

Dr. Pulsipher reported relationships with Adaptive Biotech, Novartis, Incyte, Amgen, Bellicum Pharmaceuticals, Medac Pharma, and Miltenyi Biotec. ELIANA and ENSIGN were funded by Novartis, which markets tisagenlecleucel as Kymriah.

[email protected]

SOURCE: Pulsipher MA et al. ASPHO 2019, Abstract 2001.

NEW ORLEANS – Next-generation sequencing of peripheral blood is at least as effective as flow cytometry of bone marrow for assessing minimal residual disease, according to a new study.

Researchers compared bone marrow flow cytometry (FC) and peripheral blood next-generation sequencing (NGS) for minimal residual disease (MRD) assessment in pediatric and young adult patients with B-cell acute lymphoblastic leukemia (B-ALL) who received treatment with tisagenlecleucel. There was a high level of concordance between the assays, but the NGS assay detected more MRD-positive samples and NGS results provided a longer lead time to relapse.

Michael A. Pulsipher, MD, of the Children’s Hospital Los Angeles, presented these results at the annual meeting of the American Society of Pediatric Hematology/Oncology.

The researchers analyzed samples from pediatric and young adult patients aged 2-25 years who had relapsed or refractory B-ALL and received treatment with tisagenlecleucel on the ELIANA or ENSIGN trials.

The patients had received at least two prior lines of therapy and were ineligible for allogeneic transplant. They received a single dose of tisagenlecleucel. MRD was assessed before tisagenlecleucel infusion, at various time points after infusion, and at relapse.

Dr. Pulsipher and his colleagues compared MRD results from an NGS assay – Adaptive Biotechnologies’ clonoSEQ – using peripheral blood and results from FC of bone marrow. NGS and FC results were available for 237 samples from 83 patients.

After treatment, NGS detected more MRD-positive samples at each sensitivity level tested (10^-4, 10^-5, and 10^-6). At 10^-6, NGS detected 18% more MRD-positive samples than did FC – 50% and 32%, respectively.

Detection of MRD positivity prior to relapse was faster with NGS than with FC. In 17 of 34 patients with morphological relapse, NGS provided a median lead time of 67 days. FC provided a median lead time of 39 days in 11 of the 34 patients.

About 80% of patients who had an MRD status of zero by NGS at day 28 remained relapse-free for up to 3 years.

Among complete responders (n = 50), the duration of response was significantly longer in patients who had an MRD status of zero at day 28 by NGS than in patients who had an MRD status greater than zero (P = .0003). Overall survival was significantly better among patients with an MRD status of zero as well (P = .0004).

Dr. Pulsipher said additional studies are needed to confirm these findings and determine the best way to know if a patient has been cured or needs additional therapy after tisagenlecleucel.

Dr. Pulsipher reported relationships with Adaptive Biotech, Novartis, Incyte, Amgen, Bellicum Pharmaceuticals, Medac Pharma, and Miltenyi Biotec. ELIANA and ENSIGN were funded by Novartis, which markets tisagenlecleucel as Kymriah.

[email protected]

SOURCE: Pulsipher MA et al. ASPHO 2019, Abstract 2001.

NEW ORLEANS – Next-generation sequencing of peripheral blood is at least as effective as flow cytometry of bone marrow for assessing minimal residual disease, according to a new study.

Researchers compared bone marrow flow cytometry (FC) and peripheral blood next-generation sequencing (NGS) for minimal residual disease (MRD) assessment in pediatric and young adult patients with B-cell acute lymphoblastic leukemia (B-ALL) who received treatment with tisagenlecleucel. There was a high level of concordance between the assays, but the NGS assay detected more MRD-positive samples and NGS results provided a longer lead time to relapse.

Michael A. Pulsipher, MD, of the Children’s Hospital Los Angeles, presented these results at the annual meeting of the American Society of Pediatric Hematology/Oncology.

The researchers analyzed samples from pediatric and young adult patients aged 2-25 years who had relapsed or refractory B-ALL and received treatment with tisagenlecleucel on the ELIANA or ENSIGN trials.

The patients had received at least two prior lines of therapy and were ineligible for allogeneic transplant. They received a single dose of tisagenlecleucel. MRD was assessed before tisagenlecleucel infusion, at various time points after infusion, and at relapse.

Dr. Pulsipher and his colleagues compared MRD results from an NGS assay – Adaptive Biotechnologies’ clonoSEQ – using peripheral blood and results from FC of bone marrow. NGS and FC results were available for 237 samples from 83 patients.

After treatment, NGS detected more MRD-positive samples at each sensitivity level tested (10^-4, 10^-5, and 10^-6). At 10^-6, NGS detected 18% more MRD-positive samples than did FC – 50% and 32%, respectively.

Detection of MRD positivity prior to relapse was faster with NGS than with FC. In 17 of 34 patients with morphological relapse, NGS provided a median lead time of 67 days. FC provided a median lead time of 39 days in 11 of the 34 patients.

About 80% of patients who had an MRD status of zero by NGS at day 28 remained relapse-free for up to 3 years.

Among complete responders (n = 50), the duration of response was significantly longer in patients who had an MRD status of zero at day 28 by NGS than in patients who had an MRD status greater than zero (P = .0003). Overall survival was significantly better among patients with an MRD status of zero as well (P = .0004).

Dr. Pulsipher said additional studies are needed to confirm these findings and determine the best way to know if a patient has been cured or needs additional therapy after tisagenlecleucel.

Dr. Pulsipher reported relationships with Adaptive Biotech, Novartis, Incyte, Amgen, Bellicum Pharmaceuticals, Medac Pharma, and Miltenyi Biotec. ELIANA and ENSIGN were funded by Novartis, which markets tisagenlecleucel as Kymriah.

[email protected]

SOURCE: Pulsipher MA et al. ASPHO 2019, Abstract 2001.

The Food and Drug Administration has approved the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.

The approval provides a chemotherapy-free, fixed duration treatment. The FDA based the approval on the results of the phase 3 CLL14 trial, which will be presented at the 2019 annual meeting of the American Society of Clinical Oncology.

Researchers randomized 432 patients to either a 12-month duration of venetoclax with a 6-month duration of obinutuzumab or to a 6-month duration of obinutuzumab plus chlorambucil and another 6-month duration of chlorambucil.

The newly approved combination reduced the risk of disease progression or death (progression-free survival as assessed by an independent review committee) by 67%, compared with obinutuzumab/chlorambucil (hazard ratio, 0.33; P less than .0001).

Venetoclax/obinutuzumab also had a higher rate of minimal residual disease negativity in bone marrow and peripheral blood, compared to the other combination, according to Genentech.

The most common adverse reactions of any grade reported for venetoclax/obinutuzumab were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.

[email protected]

The Food and Drug Administration has approved the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.

The approval provides a chemotherapy-free, fixed duration treatment. The FDA based the approval on the results of the phase 3 CLL14 trial, which will be presented at the 2019 annual meeting of the American Society of Clinical Oncology.

Researchers randomized 432 patients to either a 12-month duration of venetoclax with a 6-month duration of obinutuzumab or to a 6-month duration of obinutuzumab plus chlorambucil and another 6-month duration of chlorambucil.

The newly approved combination reduced the risk of disease progression or death (progression-free survival as assessed by an independent review committee) by 67%, compared with obinutuzumab/chlorambucil (hazard ratio, 0.33; P less than .0001).

Venetoclax/obinutuzumab also had a higher rate of minimal residual disease negativity in bone marrow and peripheral blood, compared to the other combination, according to Genentech.

The most common adverse reactions of any grade reported for venetoclax/obinutuzumab were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.

[email protected]

The Food and Drug Administration has approved the combination of venetoclax (Venclexta) plus obinutuzumab (Gazyva) for patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.

The approval provides a chemotherapy-free, fixed duration treatment. The FDA based the approval on the results of the phase 3 CLL14 trial, which will be presented at the 2019 annual meeting of the American Society of Clinical Oncology.

Researchers randomized 432 patients to either a 12-month duration of venetoclax with a 6-month duration of obinutuzumab or to a 6-month duration of obinutuzumab plus chlorambucil and another 6-month duration of chlorambucil.

The newly approved combination reduced the risk of disease progression or death (progression-free survival as assessed by an independent review committee) by 67%, compared with obinutuzumab/chlorambucil (hazard ratio, 0.33; P less than .0001).

Venetoclax/obinutuzumab also had a higher rate of minimal residual disease negativity in bone marrow and peripheral blood, compared to the other combination, according to Genentech.

The most common adverse reactions of any grade reported for venetoclax/obinutuzumab were neutropenia, diarrhea, fatigue, nausea, anemia, and upper respiratory tract infection.

[email protected]

Hematopoietic stem cell transplantation (HSCT) is increasingly being used to treat hematologic malignancies as well as nonmalignant diseases and solid tumors. Over the past 2 decades overall survival following transplant and transplant-related mortality have improved.¹ With this increased survival, there is a need to focus on late complications after transplantation. Pulmonary complications are a common but sometimes underrecognized cause of late morbidity and mortality in HSCT patients. This article, the second of 2 articles on post-HSCT pulmonary complications, reviews late-onset complications, with a focus on the evaluation and treatment of bronchiolitis obliterans syndrome (BOS), one of the most common and serious late pulmonary complications in HSCT patients. The first article reviewed the management of early-onset pulmonary complications and included a basic overview of stem cell transplantation, discussion of factors associated with pulmonary complications, and a review of methods for assessing pretransplant risk for pulmonary complications in patients undergoing HSCT.²

Case Presentation

A 40-year-old white woman with a history of acute myeloid leukemia status post peripheral blood stem cell transplant presents with dyspnea on exertion, which she states started about 1 month ago and now is limiting her with even 1 flight of stairs. She also complains of mild dry cough and a 4- to 5-lb weight loss over the past 1 to 2 months. She has an occasional runny nose, but denies gastroesophageal reflux, fevers, chills, or night sweats. She has a history of matched related sibling donor transplant with busulfan and cyclophosphamide conditioning 1 year prior to presentation. She has had significant graft-versus-host disease (GVHD), affecting the liver, gastrointestinal tract, skin, and eyes.

On physical examination, heart rate is 110 beats/min, respiratory rate is 16 breaths/min, blood pressure is 92/58 mm Hg, and the patient is afebrile. Eye exam reveals scleral injection, mouth shows dry mucous membranes with a few white plaques, and the skin has chronic changes with a rash over both arms. Cardiac exam reveals tachycardia but regular rhythm and there are no murmurs, rubs, or gallops. Lungs are clear bilaterally and abdomen shows no organomegaly.

Laboratory exam shows a white blood cell count of 7800 cells/μL, hemoglobin level of 12.4 g/dL, and platelet count of 186 × 10³/μL. Liver enzymes are mildly elevated. Chest radiograph shows clear lung fields bilaterally.

• What is the differential in this patient with dyspnea 1 year after transplantation?

Late pulmonary complications are generally accepted as those occurring more than 100 days post transplant. This period of time is characterized by chronic GVHD and impaired cellular and humoral immunity. Results of longitudinal studies of infections in adult HSCT patients suggest that special attention should be paid to allogeneic HSCT recipients for post-engraftment infectious pulmonary complications.³ Encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae are the most frequent bacterial organisms causing late infectious pulmonary complications. Nontuberculous mycobacteria and Nocardia should also be considered. Depending upon geographic location, social and occupational risk factors, and prevalence, tuberculosis should also enter the differential.

There are many noninfectious late-onset pulmonary complications after HSCT. Unfortunately, the literature has divided pulmonary complications after HSCT using a range of criteria and classifications based upon timing, predominant pulmonary function test (PFT) findings, and etiology. These include early versus late, obstructive versus restrictive, and infectious versus noninfectious, which makes a comprehensive literature review of late pulmonary complications difficult. The most common noninfectious late-onset complications are bronchiolitis obliterans, cryptogenic organizing pneumonia (previously referred to as bronchiolitis obliterans organizing pneumonia, or BOOP), and interstitial pneumonia. Other rarely reported complications include eosinophilic pneumonia, pulmonary alveolar proteinosis, air leak syndrome, and pulmonary hypertension.

Case Continued

Because the patient does not have symptoms of infection, PFTs are obtained. Pretransplant PFTs and current PFTs are shown in Table 1.

• What is the diagnosis in this case?

Bronchiolitis Obliterans

BOS is one of the most common and most serious late-onset pulmonary diseases after allogeneic transplantation. It is considered the pulmonary form of chronic GVHD. BOS was first described in 1982 in patients with chronic GVHD after bone marrow transplantation.⁴ Many differing definitions of bronchiolitis obliterans have been described in the literature. A recent review of the topic cites 10 different published sets of criteria for the diagnosis of bronchiolitis obliterans.⁵ Traditionally, bronchiolitis obliterans was thought to occur in 2% to 8% of patients undergoing allogeneic HSCT, but these findings were from older studies that used a diagnosis based on very specific pathology findings. When more liberal diagnostic criteria are used, the incidence may be as high as 26% of allogeneic HSCT patients.⁶

Bronchiolitis obliterans is a progressive lung disease characterized by narrowing of the terminal airways and obliteration of the terminal bronchi. Pathology may show constrictive bronchiolitis but can also show lymphocytic bronchiolitis, which may be associated with a better outcome.⁷ As noted, bronchiolitis obliterans has traditionally been considered a pathologic diagnosis. Current diagnostic criteria have evolved based upon the difficulty in obtaining this diagnosis through transbronchial biopsy given the patchy nature of the disease.⁸ The gold standard of open lung biopsy is seldom pursued in the post-HSCT population as the procedure continues to carry a worrisome risk-benefit profile.

The 2005 National Institutes of Health (NIH) consensus development project on criteria for clinical trials in chronic GVHD developed a clinical strategy for diagnosing BOS using the following criteria: absence of active infection, decreased forced expiratory volume in 1 second (FEV₁) < 75%, FEV₁/forced vital capacity (FVC) ratio of < 70%, and evidence of air trapping on high-resolution computed tomography (HRCT) or PFTs (residual volume > 120%). These diagnostic criteria were applied to a small series of patients with clinically identified bronchiolitis obliterans or biopsy-proven bronchiolitis obliterans. Only 18% of these patients met the requirements for the NIH consensus definition.⁵ A 2011 study that applied the NIH criteria found an overall prevalence of 5.5% among all transplant recipients but a prevalence of 14% in patients with GVHD.⁹ In 2014, the NIH consensus development group updated their recommendations. The new criteria for diagnosis of BOS require the presence of  airflow obstruction (FEV₁/FVC < 70% or 5^th percentile of predicted), FEV₁ < 75% predicted with a ≥ 10% decline in fewer than 2 years, absence of infection, and presence of air trapping (by expiratory computed tomography [CT] scan or PFT with residual volume >120% predicted) (Table 2).

Some issues must be considered when determining airflow obstruction. The 2005 NIH working group recommends using Crapo as the reference set,¹¹ but the National Health and Nutrition Examination Survey (NHANES) III reference values are the preferred reference set at this time¹² and should be used in the United States. A recent article showed that the NHANES values were superior to older reference sets (however, they did not use Crapo as the comparison), although this study used the lower limit of normal as compared with the fixed 70% ratio.¹³ The 2014 NIH consensus group does not recommend a specific reference set and recognizes an FEV₁/FVC ratio of 70% or less than the lower limit of normal as the cutoff value for airflow obstruction.¹⁰

Another issue in PFT interpretation is the finding of a decrease in FEV1 and FVC and normal total lung capacity, which is termed a nonspecific pattern. This pattern has been reported to occur in 9% of all PFTs and usually is associated with obstructive lung disease or obesity.¹⁴ A 2013 study described the nonspecific pattern as a BOS subgroup occurring in up to 31% of bronchiolitis obliterans patients.¹⁵

• What are the radiographic findings of BOS?

Chest radiograph is often normal in BOS. As discussed, air trapping can be documented using HRCT, according to the NIH clinical definition of bronchiolitis obliterans.¹⁶ A study that explored findings and trends seen on HRCT in HSCT patients with BOS found that the syndrome in these patients is characterized by central airway dilatation.¹⁷ Expiratory airway trapping on HRCT is the main finding, and this is best demonstrated on HRCT during inspiratory and expiratory phases.¹⁸ Other findings are bronchial wall thickening, parenchymal hypoattenuation, bronchiectasis, and centrilobular nodules.¹⁹

Galbán and colleagues developed a new technique called parametric response mapping that uses CT scanners to quantify normal parenchyma, functional small airway disease, emphysema, and parenchymal disease as relative lung volumes.²⁰ This technique can detect airflow obstruction and small airway disease and was found to be a good method for detecting BOS after HSCT. In their study of parametric response mapping, the authors found that functional small airway disease affecting 28% or more of the total lung was highly indicative of bronchiolitis obliterans.²⁰

• What therapies are used to treat BOS?

Traditionally, BOS has been treated with systemic immunosuppression. The recommended treatment had been systemic steroids at approximately 1 mg/ kg. However, it is increasingly recognized that BOS responds poorly to systemic steroids, and systemic steroids may actually be harmful and associated with increased mortality.^15,21 The chronic GVHD recommendations from 2005 recommend ancillary therapy with inhaled corticosteroids and pulmonary rehabilitation.¹¹ The updated 2011 German consensus statement lays out a clear management strategy for mild and moderate-severe disease with monitoring recommendations.²² The 2014 NIH chronic GVHD working group recommends fluticasone, azithromycin, and montelukast (ie, the FAM protocol) for treating BOS.²³ FAM therapy in BOS may help lower the systemic steroid dose.^24,25 Montelukast is not considered a treatment mainstay for BOS after lung transplant, but there is a study showing possible benefit in chronic GVHD.²⁶ An evaluation of the natural history of a cohort of BOS patients treated with FAM therapy showed a rapid decline of FEV₁ in the 6 months prior to diagnosis and treatment of BOS and subsequent stabilization following diagnosis and treatment.²⁷ The benefit of high-dose inhaled corticosteroids or the combination of inhaled corticosteroids and long-acting beta-agonists has been demonstrated in small studies, which showed that these agents stabilized FEV₁ and avoided the untoward side effects of systemic corticosteroids.^28–30

Macrolide antibiotics have been explored as a treatment for BOS post HSCT because pilot studies suggested that azithromycin improved or stabilized FEV₁ in patients with BOS after lung transplant or HSCT.^31–33 Other studies of azithromycin have not shown benefit in the HSCT population after 3 months of therapy.³⁴ A recent meta-analysis could neither support or refute the benefit of azithromycin for BOS after HSCT.³⁵ In the lung transplant population, a study showed that patients who were started on azithromycin after transplant and continued on it 3 times a week had improved FEV₁; these patients also had a reduced rate of BOS and improved overall and BOS-free survival 2 years after transplant.³⁶ However, these benefits of azithromycin have not been observed in patients after HSCT. In fact, the ALLOZITHRO trial was stopped early because prophylactic azithromycin started at the time of the conditioning regimen with HSCT was associated with increased hematologic disease relapse, a decrease in airflow-decline-free survival, and reduced 2-year survival.³⁰

Azithromycin is believed to exert an effect by its anti-inflammatory properties and perhaps by decreasing lung neutrophilia (it may be most beneficial in the subset of patients with high neutrophilia on bronchoalveolar lavage [BAL]).³⁰ Adverse effects of chronic azithromycin include QT prolongation, cardiac arrhythmia, hearing loss, and antibiotic-resistant organism colonization.^37,38

Other therapies include pulmonary rehabilitation, which may improve health-related quality of life and 6-minute walk distance,³⁹ extracorporeal photopheresis,⁴⁰ immunosuppression with calcineurin inhibitors or mycophenolate mofetil,^21,41 and lung transplantation.^42–44 A study with imatinib for the treatment of lung disease in steroid-refractory GVHD has shown promising results, but further validation with larger clinical trials is required.⁴⁵

Case Continued

The patient is diagnosed with BOS and is treated for several months with prednisone 40 mg/day weaned over 3 months. She is started on inhaled corticosteroids, a proton pump inhibitor, and azithromycin 3 times per week, but she has a progressive decline in FEV₁.  She starts pulmonary rehabilitation but continues to functionally decline. Over the next year she develops bilateral pneumothoraces and bilateral cavitary nodules (Figure 1).

• What is causing this decline and the radiographic abnormalities?

Spontaneous air leak syndrome has been described in a little more than 1% of patients undergoing HSCT and has included pneumothorax and mediastinal and subcutaneous emphysema.⁴⁶ It appears that air leak syndrome is more likely to occur in patients with chronic GVHD.⁴⁷ The association between chronic GVHD and air leak syndrome could explain this patient’s recurrent pneumothoraces. The recurrent cavitary nodules are suspicious for infectious etiologies such as nontuberculous mycobacteria, tuberculosis, and fungal infections.

Case Continued

During an episode of pneumothorax, the patient undergoes chest tube placement, pleurodesis, and lung biopsy.  Pathology reveals bronchiolitis obliterans as well as organizing pneumonia (Figure 2). No organisms are seen on acid-fast bacilli or GMS stains.

• What are the other late-onset noninfectious pulmonary complications?

Definitions of other late noninfectious pulmonary complications following HSCT are shown in Table 3.

Interstitial pneumonias may represent COP or may be idiopathic pneumonia syndrome with a later onset or a nonspecific interstitial pneumonia. This syndrome is poorly defined, with a number of differing definitions of the syndrome published in the literature.^50–55

A rare pulmonary complication after HSCT is pulmonary veno-occlusive disease (PVOD). Pulmonary hypertension has been reported after HSCT,⁵⁶ but PVOD is a subset of pulmonary hypertension. It is associated with pleural effusions and volume overload on chest radiography.^57,58 It may present early or late after transplant and is poorly understood.

Besides obstructive and restrictive PFT abnormalities, changes in small airway function⁵⁹ after transplant and loss in diffusing capacity of the lungs for carbon monoxide (Dlco) in the first 5 years after transplant have been reported, although these parameters improve by 10 years after transplant.⁶⁰ There do not appear to be any changes in responsiveness to methacholine.⁶¹ Losses in respiratory muscle strength (PiMax and PeMax after transplant) have been reported.⁶² Lower aerobic exercise capacity (Vo₂max) after pediatric HSCT has also been reported.⁶³

Case Conclusion

The patient’s lung function continues to worsen, but no infectious etiologies are discovered. Ultimately, she dies of respiratory failure caused by progressive bronchiolitis obliterans.

Conclusion

Late pulmonary complications occur frequently in patients who have undergone HSCT. These complications can be classified as infectious versus noninfectious etiologies. Late-onset complications are more common in allogeneic transplantations because they are associated with chronic GVHD. These complications can be manifestations of pulmonary GHVD or can be infectious complications associated with prolonged immunosuppression. Appropriate monitoring for the development of BOS is essential. Early and aggressive treatment of respiratory infections and diagnostic bronchoscopy with BAL can help elucidate most infectious causes. Still, diagnostic challenges remain and multiple causes of respiratory deterioration can be present concurrently in the post-HSCT patient. Steroid therapy remains the mainstay treatment for most noninfectious pulmonary complications and should be strongly considered once infection is effectively ruled out.

Hematopoietic stem cell transplantation (HSCT) is increasingly being used to treat hematologic malignancies as well as nonmalignant diseases and solid tumors. Over the past 2 decades overall survival following transplant and transplant-related mortality have improved.¹ With this increased survival, there is a need to focus on late complications after transplantation. Pulmonary complications are a common but sometimes underrecognized cause of late morbidity and mortality in HSCT patients. This article, the second of 2 articles on post-HSCT pulmonary complications, reviews late-onset complications, with a focus on the evaluation and treatment of bronchiolitis obliterans syndrome (BOS), one of the most common and serious late pulmonary complications in HSCT patients. The first article reviewed the management of early-onset pulmonary complications and included a basic overview of stem cell transplantation, discussion of factors associated with pulmonary complications, and a review of methods for assessing pretransplant risk for pulmonary complications in patients undergoing HSCT.²

Case Presentation

A 40-year-old white woman with a history of acute myeloid leukemia status post peripheral blood stem cell transplant presents with dyspnea on exertion, which she states started about 1 month ago and now is limiting her with even 1 flight of stairs. She also complains of mild dry cough and a 4- to 5-lb weight loss over the past 1 to 2 months. She has an occasional runny nose, but denies gastroesophageal reflux, fevers, chills, or night sweats. She has a history of matched related sibling donor transplant with busulfan and cyclophosphamide conditioning 1 year prior to presentation. She has had significant graft-versus-host disease (GVHD), affecting the liver, gastrointestinal tract, skin, and eyes.

On physical examination, heart rate is 110 beats/min, respiratory rate is 16 breaths/min, blood pressure is 92/58 mm Hg, and the patient is afebrile. Eye exam reveals scleral injection, mouth shows dry mucous membranes with a few white plaques, and the skin has chronic changes with a rash over both arms. Cardiac exam reveals tachycardia but regular rhythm and there are no murmurs, rubs, or gallops. Lungs are clear bilaterally and abdomen shows no organomegaly.

Laboratory exam shows a white blood cell count of 7800 cells/μL, hemoglobin level of 12.4 g/dL, and platelet count of 186 × 10³/μL. Liver enzymes are mildly elevated. Chest radiograph shows clear lung fields bilaterally.

• What is the differential in this patient with dyspnea 1 year after transplantation?

Late pulmonary complications are generally accepted as those occurring more than 100 days post transplant. This period of time is characterized by chronic GVHD and impaired cellular and humoral immunity. Results of longitudinal studies of infections in adult HSCT patients suggest that special attention should be paid to allogeneic HSCT recipients for post-engraftment infectious pulmonary complications.³ Encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae are the most frequent bacterial organisms causing late infectious pulmonary complications. Nontuberculous mycobacteria and Nocardia should also be considered. Depending upon geographic location, social and occupational risk factors, and prevalence, tuberculosis should also enter the differential.

There are many noninfectious late-onset pulmonary complications after HSCT. Unfortunately, the literature has divided pulmonary complications after HSCT using a range of criteria and classifications based upon timing, predominant pulmonary function test (PFT) findings, and etiology. These include early versus late, obstructive versus restrictive, and infectious versus noninfectious, which makes a comprehensive literature review of late pulmonary complications difficult. The most common noninfectious late-onset complications are bronchiolitis obliterans, cryptogenic organizing pneumonia (previously referred to as bronchiolitis obliterans organizing pneumonia, or BOOP), and interstitial pneumonia. Other rarely reported complications include eosinophilic pneumonia, pulmonary alveolar proteinosis, air leak syndrome, and pulmonary hypertension.

Case Continued

Because the patient does not have symptoms of infection, PFTs are obtained. Pretransplant PFTs and current PFTs are shown in Table 1.

• What is the diagnosis in this case?

Bronchiolitis Obliterans

BOS is one of the most common and most serious late-onset pulmonary diseases after allogeneic transplantation. It is considered the pulmonary form of chronic GVHD. BOS was first described in 1982 in patients with chronic GVHD after bone marrow transplantation.⁴ Many differing definitions of bronchiolitis obliterans have been described in the literature. A recent review of the topic cites 10 different published sets of criteria for the diagnosis of bronchiolitis obliterans.⁵ Traditionally, bronchiolitis obliterans was thought to occur in 2% to 8% of patients undergoing allogeneic HSCT, but these findings were from older studies that used a diagnosis based on very specific pathology findings. When more liberal diagnostic criteria are used, the incidence may be as high as 26% of allogeneic HSCT patients.⁶

Bronchiolitis obliterans is a progressive lung disease characterized by narrowing of the terminal airways and obliteration of the terminal bronchi. Pathology may show constrictive bronchiolitis but can also show lymphocytic bronchiolitis, which may be associated with a better outcome.⁷ As noted, bronchiolitis obliterans has traditionally been considered a pathologic diagnosis. Current diagnostic criteria have evolved based upon the difficulty in obtaining this diagnosis through transbronchial biopsy given the patchy nature of the disease.⁸ The gold standard of open lung biopsy is seldom pursued in the post-HSCT population as the procedure continues to carry a worrisome risk-benefit profile.

The 2005 National Institutes of Health (NIH) consensus development project on criteria for clinical trials in chronic GVHD developed a clinical strategy for diagnosing BOS using the following criteria: absence of active infection, decreased forced expiratory volume in 1 second (FEV₁) < 75%, FEV₁/forced vital capacity (FVC) ratio of < 70%, and evidence of air trapping on high-resolution computed tomography (HRCT) or PFTs (residual volume > 120%). These diagnostic criteria were applied to a small series of patients with clinically identified bronchiolitis obliterans or biopsy-proven bronchiolitis obliterans. Only 18% of these patients met the requirements for the NIH consensus definition.⁵ A 2011 study that applied the NIH criteria found an overall prevalence of 5.5% among all transplant recipients but a prevalence of 14% in patients with GVHD.⁹ In 2014, the NIH consensus development group updated their recommendations. The new criteria for diagnosis of BOS require the presence of  airflow obstruction (FEV₁/FVC < 70% or 5^th percentile of predicted), FEV₁ < 75% predicted with a ≥ 10% decline in fewer than 2 years, absence of infection, and presence of air trapping (by expiratory computed tomography [CT] scan or PFT with residual volume >120% predicted) (Table 2).

Some issues must be considered when determining airflow obstruction. The 2005 NIH working group recommends using Crapo as the reference set,¹¹ but the National Health and Nutrition Examination Survey (NHANES) III reference values are the preferred reference set at this time¹² and should be used in the United States. A recent article showed that the NHANES values were superior to older reference sets (however, they did not use Crapo as the comparison), although this study used the lower limit of normal as compared with the fixed 70% ratio.¹³ The 2014 NIH consensus group does not recommend a specific reference set and recognizes an FEV₁/FVC ratio of 70% or less than the lower limit of normal as the cutoff value for airflow obstruction.¹⁰

Another issue in PFT interpretation is the finding of a decrease in FEV1 and FVC and normal total lung capacity, which is termed a nonspecific pattern. This pattern has been reported to occur in 9% of all PFTs and usually is associated with obstructive lung disease or obesity.¹⁴ A 2013 study described the nonspecific pattern as a BOS subgroup occurring in up to 31% of bronchiolitis obliterans patients.¹⁵

• What are the radiographic findings of BOS?

Chest radiograph is often normal in BOS. As discussed, air trapping can be documented using HRCT, according to the NIH clinical definition of bronchiolitis obliterans.¹⁶ A study that explored findings and trends seen on HRCT in HSCT patients with BOS found that the syndrome in these patients is characterized by central airway dilatation.¹⁷ Expiratory airway trapping on HRCT is the main finding, and this is best demonstrated on HRCT during inspiratory and expiratory phases.¹⁸ Other findings are bronchial wall thickening, parenchymal hypoattenuation, bronchiectasis, and centrilobular nodules.¹⁹

Galbán and colleagues developed a new technique called parametric response mapping that uses CT scanners to quantify normal parenchyma, functional small airway disease, emphysema, and parenchymal disease as relative lung volumes.²⁰ This technique can detect airflow obstruction and small airway disease and was found to be a good method for detecting BOS after HSCT. In their study of parametric response mapping, the authors found that functional small airway disease affecting 28% or more of the total lung was highly indicative of bronchiolitis obliterans.²⁰

• What therapies are used to treat BOS?

Traditionally, BOS has been treated with systemic immunosuppression. The recommended treatment had been systemic steroids at approximately 1 mg/ kg. However, it is increasingly recognized that BOS responds poorly to systemic steroids, and systemic steroids may actually be harmful and associated with increased mortality.^15,21 The chronic GVHD recommendations from 2005 recommend ancillary therapy with inhaled corticosteroids and pulmonary rehabilitation.¹¹ The updated 2011 German consensus statement lays out a clear management strategy for mild and moderate-severe disease with monitoring recommendations.²² The 2014 NIH chronic GVHD working group recommends fluticasone, azithromycin, and montelukast (ie, the FAM protocol) for treating BOS.²³ FAM therapy in BOS may help lower the systemic steroid dose.^24,25 Montelukast is not considered a treatment mainstay for BOS after lung transplant, but there is a study showing possible benefit in chronic GVHD.²⁶ An evaluation of the natural history of a cohort of BOS patients treated with FAM therapy showed a rapid decline of FEV₁ in the 6 months prior to diagnosis and treatment of BOS and subsequent stabilization following diagnosis and treatment.²⁷ The benefit of high-dose inhaled corticosteroids or the combination of inhaled corticosteroids and long-acting beta-agonists has been demonstrated in small studies, which showed that these agents stabilized FEV₁ and avoided the untoward side effects of systemic corticosteroids.^28–30

Macrolide antibiotics have been explored as a treatment for BOS post HSCT because pilot studies suggested that azithromycin improved or stabilized FEV₁ in patients with BOS after lung transplant or HSCT.^31–33 Other studies of azithromycin have not shown benefit in the HSCT population after 3 months of therapy.³⁴ A recent meta-analysis could neither support or refute the benefit of azithromycin for BOS after HSCT.³⁵ In the lung transplant population, a study showed that patients who were started on azithromycin after transplant and continued on it 3 times a week had improved FEV₁; these patients also had a reduced rate of BOS and improved overall and BOS-free survival 2 years after transplant.³⁶ However, these benefits of azithromycin have not been observed in patients after HSCT. In fact, the ALLOZITHRO trial was stopped early because prophylactic azithromycin started at the time of the conditioning regimen with HSCT was associated with increased hematologic disease relapse, a decrease in airflow-decline-free survival, and reduced 2-year survival.³⁰

Azithromycin is believed to exert an effect by its anti-inflammatory properties and perhaps by decreasing lung neutrophilia (it may be most beneficial in the subset of patients with high neutrophilia on bronchoalveolar lavage [BAL]).³⁰ Adverse effects of chronic azithromycin include QT prolongation, cardiac arrhythmia, hearing loss, and antibiotic-resistant organism colonization.^37,38

Other therapies include pulmonary rehabilitation, which may improve health-related quality of life and 6-minute walk distance,³⁹ extracorporeal photopheresis,⁴⁰ immunosuppression with calcineurin inhibitors or mycophenolate mofetil,^21,41 and lung transplantation.^42–44 A study with imatinib for the treatment of lung disease in steroid-refractory GVHD has shown promising results, but further validation with larger clinical trials is required.⁴⁵

Case Continued

The patient is diagnosed with BOS and is treated for several months with prednisone 40 mg/day weaned over 3 months. She is started on inhaled corticosteroids, a proton pump inhibitor, and azithromycin 3 times per week, but she has a progressive decline in FEV₁.  She starts pulmonary rehabilitation but continues to functionally decline. Over the next year she develops bilateral pneumothoraces and bilateral cavitary nodules (Figure 1).

• What is causing this decline and the radiographic abnormalities?

Spontaneous air leak syndrome has been described in a little more than 1% of patients undergoing HSCT and has included pneumothorax and mediastinal and subcutaneous emphysema.⁴⁶ It appears that air leak syndrome is more likely to occur in patients with chronic GVHD.⁴⁷ The association between chronic GVHD and air leak syndrome could explain this patient’s recurrent pneumothoraces. The recurrent cavitary nodules are suspicious for infectious etiologies such as nontuberculous mycobacteria, tuberculosis, and fungal infections.

Case Continued

During an episode of pneumothorax, the patient undergoes chest tube placement, pleurodesis, and lung biopsy.  Pathology reveals bronchiolitis obliterans as well as organizing pneumonia (Figure 2). No organisms are seen on acid-fast bacilli or GMS stains.

• What are the other late-onset noninfectious pulmonary complications?

Definitions of other late noninfectious pulmonary complications following HSCT are shown in Table 3.

Interstitial pneumonias may represent COP or may be idiopathic pneumonia syndrome with a later onset or a nonspecific interstitial pneumonia. This syndrome is poorly defined, with a number of differing definitions of the syndrome published in the literature.^50–55

A rare pulmonary complication after HSCT is pulmonary veno-occlusive disease (PVOD). Pulmonary hypertension has been reported after HSCT,⁵⁶ but PVOD is a subset of pulmonary hypertension. It is associated with pleural effusions and volume overload on chest radiography.^57,58 It may present early or late after transplant and is poorly understood.

Besides obstructive and restrictive PFT abnormalities, changes in small airway function⁵⁹ after transplant and loss in diffusing capacity of the lungs for carbon monoxide (Dlco) in the first 5 years after transplant have been reported, although these parameters improve by 10 years after transplant.⁶⁰ There do not appear to be any changes in responsiveness to methacholine.⁶¹ Losses in respiratory muscle strength (PiMax and PeMax after transplant) have been reported.⁶² Lower aerobic exercise capacity (Vo₂max) after pediatric HSCT has also been reported.⁶³

Case Conclusion

The patient’s lung function continues to worsen, but no infectious etiologies are discovered. Ultimately, she dies of respiratory failure caused by progressive bronchiolitis obliterans.

Conclusion

Late pulmonary complications occur frequently in patients who have undergone HSCT. These complications can be classified as infectious versus noninfectious etiologies. Late-onset complications are more common in allogeneic transplantations because they are associated with chronic GVHD. These complications can be manifestations of pulmonary GHVD or can be infectious complications associated with prolonged immunosuppression. Appropriate monitoring for the development of BOS is essential. Early and aggressive treatment of respiratory infections and diagnostic bronchoscopy with BAL can help elucidate most infectious causes. Still, diagnostic challenges remain and multiple causes of respiratory deterioration can be present concurrently in the post-HSCT patient. Steroid therapy remains the mainstay treatment for most noninfectious pulmonary complications and should be strongly considered once infection is effectively ruled out.

Hematopoietic stem cell transplantation (HSCT) is increasingly being used to treat hematologic malignancies as well as nonmalignant diseases and solid tumors. Over the past 2 decades overall survival following transplant and transplant-related mortality have improved.¹ With this increased survival, there is a need to focus on late complications after transplantation. Pulmonary complications are a common but sometimes underrecognized cause of late morbidity and mortality in HSCT patients. This article, the second of 2 articles on post-HSCT pulmonary complications, reviews late-onset complications, with a focus on the evaluation and treatment of bronchiolitis obliterans syndrome (BOS), one of the most common and serious late pulmonary complications in HSCT patients. The first article reviewed the management of early-onset pulmonary complications and included a basic overview of stem cell transplantation, discussion of factors associated with pulmonary complications, and a review of methods for assessing pretransplant risk for pulmonary complications in patients undergoing HSCT.²

Case Presentation

A 40-year-old white woman with a history of acute myeloid leukemia status post peripheral blood stem cell transplant presents with dyspnea on exertion, which she states started about 1 month ago and now is limiting her with even 1 flight of stairs. She also complains of mild dry cough and a 4- to 5-lb weight loss over the past 1 to 2 months. She has an occasional runny nose, but denies gastroesophageal reflux, fevers, chills, or night sweats. She has a history of matched related sibling donor transplant with busulfan and cyclophosphamide conditioning 1 year prior to presentation. She has had significant graft-versus-host disease (GVHD), affecting the liver, gastrointestinal tract, skin, and eyes.

On physical examination, heart rate is 110 beats/min, respiratory rate is 16 breaths/min, blood pressure is 92/58 mm Hg, and the patient is afebrile. Eye exam reveals scleral injection, mouth shows dry mucous membranes with a few white plaques, and the skin has chronic changes with a rash over both arms. Cardiac exam reveals tachycardia but regular rhythm and there are no murmurs, rubs, or gallops. Lungs are clear bilaterally and abdomen shows no organomegaly.

Laboratory exam shows a white blood cell count of 7800 cells/μL, hemoglobin level of 12.4 g/dL, and platelet count of 186 × 10³/μL. Liver enzymes are mildly elevated. Chest radiograph shows clear lung fields bilaterally.

• What is the differential in this patient with dyspnea 1 year after transplantation?

Late pulmonary complications are generally accepted as those occurring more than 100 days post transplant. This period of time is characterized by chronic GVHD and impaired cellular and humoral immunity. Results of longitudinal studies of infections in adult HSCT patients suggest that special attention should be paid to allogeneic HSCT recipients for post-engraftment infectious pulmonary complications.³ Encapsulated bacteria such as Haemophilus influenzae and Streptococcus pneumoniae are the most frequent bacterial organisms causing late infectious pulmonary complications. Nontuberculous mycobacteria and Nocardia should also be considered. Depending upon geographic location, social and occupational risk factors, and prevalence, tuberculosis should also enter the differential.

There are many noninfectious late-onset pulmonary complications after HSCT. Unfortunately, the literature has divided pulmonary complications after HSCT using a range of criteria and classifications based upon timing, predominant pulmonary function test (PFT) findings, and etiology. These include early versus late, obstructive versus restrictive, and infectious versus noninfectious, which makes a comprehensive literature review of late pulmonary complications difficult. The most common noninfectious late-onset complications are bronchiolitis obliterans, cryptogenic organizing pneumonia (previously referred to as bronchiolitis obliterans organizing pneumonia, or BOOP), and interstitial pneumonia. Other rarely reported complications include eosinophilic pneumonia, pulmonary alveolar proteinosis, air leak syndrome, and pulmonary hypertension.

Case Continued

Because the patient does not have symptoms of infection, PFTs are obtained. Pretransplant PFTs and current PFTs are shown in Table 1.

• What is the diagnosis in this case?

Bronchiolitis Obliterans

BOS is one of the most common and most serious late-onset pulmonary diseases after allogeneic transplantation. It is considered the pulmonary form of chronic GVHD. BOS was first described in 1982 in patients with chronic GVHD after bone marrow transplantation.⁴ Many differing definitions of bronchiolitis obliterans have been described in the literature. A recent review of the topic cites 10 different published sets of criteria for the diagnosis of bronchiolitis obliterans.⁵ Traditionally, bronchiolitis obliterans was thought to occur in 2% to 8% of patients undergoing allogeneic HSCT, but these findings were from older studies that used a diagnosis based on very specific pathology findings. When more liberal diagnostic criteria are used, the incidence may be as high as 26% of allogeneic HSCT patients.⁶

Bronchiolitis obliterans is a progressive lung disease characterized by narrowing of the terminal airways and obliteration of the terminal bronchi. Pathology may show constrictive bronchiolitis but can also show lymphocytic bronchiolitis, which may be associated with a better outcome.⁷ As noted, bronchiolitis obliterans has traditionally been considered a pathologic diagnosis. Current diagnostic criteria have evolved based upon the difficulty in obtaining this diagnosis through transbronchial biopsy given the patchy nature of the disease.⁸ The gold standard of open lung biopsy is seldom pursued in the post-HSCT population as the procedure continues to carry a worrisome risk-benefit profile.

The 2005 National Institutes of Health (NIH) consensus development project on criteria for clinical trials in chronic GVHD developed a clinical strategy for diagnosing BOS using the following criteria: absence of active infection, decreased forced expiratory volume in 1 second (FEV₁) < 75%, FEV₁/forced vital capacity (FVC) ratio of < 70%, and evidence of air trapping on high-resolution computed tomography (HRCT) or PFTs (residual volume > 120%). These diagnostic criteria were applied to a small series of patients with clinically identified bronchiolitis obliterans or biopsy-proven bronchiolitis obliterans. Only 18% of these patients met the requirements for the NIH consensus definition.⁵ A 2011 study that applied the NIH criteria found an overall prevalence of 5.5% among all transplant recipients but a prevalence of 14% in patients with GVHD.⁹ In 2014, the NIH consensus development group updated their recommendations. The new criteria for diagnosis of BOS require the presence of  airflow obstruction (FEV₁/FVC < 70% or 5^th percentile of predicted), FEV₁ < 75% predicted with a ≥ 10% decline in fewer than 2 years, absence of infection, and presence of air trapping (by expiratory computed tomography [CT] scan or PFT with residual volume >120% predicted) (Table 2).

Some issues must be considered when determining airflow obstruction. The 2005 NIH working group recommends using Crapo as the reference set,¹¹ but the National Health and Nutrition Examination Survey (NHANES) III reference values are the preferred reference set at this time¹² and should be used in the United States. A recent article showed that the NHANES values were superior to older reference sets (however, they did not use Crapo as the comparison), although this study used the lower limit of normal as compared with the fixed 70% ratio.¹³ The 2014 NIH consensus group does not recommend a specific reference set and recognizes an FEV₁/FVC ratio of 70% or less than the lower limit of normal as the cutoff value for airflow obstruction.¹⁰

Another issue in PFT interpretation is the finding of a decrease in FEV1 and FVC and normal total lung capacity, which is termed a nonspecific pattern. This pattern has been reported to occur in 9% of all PFTs and usually is associated with obstructive lung disease or obesity.¹⁴ A 2013 study described the nonspecific pattern as a BOS subgroup occurring in up to 31% of bronchiolitis obliterans patients.¹⁵

• What are the radiographic findings of BOS?

Chest radiograph is often normal in BOS. As discussed, air trapping can be documented using HRCT, according to the NIH clinical definition of bronchiolitis obliterans.¹⁶ A study that explored findings and trends seen on HRCT in HSCT patients with BOS found that the syndrome in these patients is characterized by central airway dilatation.¹⁷ Expiratory airway trapping on HRCT is the main finding, and this is best demonstrated on HRCT during inspiratory and expiratory phases.¹⁸ Other findings are bronchial wall thickening, parenchymal hypoattenuation, bronchiectasis, and centrilobular nodules.¹⁹

Galbán and colleagues developed a new technique called parametric response mapping that uses CT scanners to quantify normal parenchyma, functional small airway disease, emphysema, and parenchymal disease as relative lung volumes.²⁰ This technique can detect airflow obstruction and small airway disease and was found to be a good method for detecting BOS after HSCT. In their study of parametric response mapping, the authors found that functional small airway disease affecting 28% or more of the total lung was highly indicative of bronchiolitis obliterans.²⁰

• What therapies are used to treat BOS?

Traditionally, BOS has been treated with systemic immunosuppression. The recommended treatment had been systemic steroids at approximately 1 mg/ kg. However, it is increasingly recognized that BOS responds poorly to systemic steroids, and systemic steroids may actually be harmful and associated with increased mortality.^15,21 The chronic GVHD recommendations from 2005 recommend ancillary therapy with inhaled corticosteroids and pulmonary rehabilitation.¹¹ The updated 2011 German consensus statement lays out a clear management strategy for mild and moderate-severe disease with monitoring recommendations.²² The 2014 NIH chronic GVHD working group recommends fluticasone, azithromycin, and montelukast (ie, the FAM protocol) for treating BOS.²³ FAM therapy in BOS may help lower the systemic steroid dose.^24,25 Montelukast is not considered a treatment mainstay for BOS after lung transplant, but there is a study showing possible benefit in chronic GVHD.²⁶ An evaluation of the natural history of a cohort of BOS patients treated with FAM therapy showed a rapid decline of FEV₁ in the 6 months prior to diagnosis and treatment of BOS and subsequent stabilization following diagnosis and treatment.²⁷ The benefit of high-dose inhaled corticosteroids or the combination of inhaled corticosteroids and long-acting beta-agonists has been demonstrated in small studies, which showed that these agents stabilized FEV₁ and avoided the untoward side effects of systemic corticosteroids.^28–30

Macrolide antibiotics have been explored as a treatment for BOS post HSCT because pilot studies suggested that azithromycin improved or stabilized FEV₁ in patients with BOS after lung transplant or HSCT.^31–33 Other studies of azithromycin have not shown benefit in the HSCT population after 3 months of therapy.³⁴ A recent meta-analysis could neither support or refute the benefit of azithromycin for BOS after HSCT.³⁵ In the lung transplant population, a study showed that patients who were started on azithromycin after transplant and continued on it 3 times a week had improved FEV₁; these patients also had a reduced rate of BOS and improved overall and BOS-free survival 2 years after transplant.³⁶ However, these benefits of azithromycin have not been observed in patients after HSCT. In fact, the ALLOZITHRO trial was stopped early because prophylactic azithromycin started at the time of the conditioning regimen with HSCT was associated with increased hematologic disease relapse, a decrease in airflow-decline-free survival, and reduced 2-year survival.³⁰

Azithromycin is believed to exert an effect by its anti-inflammatory properties and perhaps by decreasing lung neutrophilia (it may be most beneficial in the subset of patients with high neutrophilia on bronchoalveolar lavage [BAL]).³⁰ Adverse effects of chronic azithromycin include QT prolongation, cardiac arrhythmia, hearing loss, and antibiotic-resistant organism colonization.^37,38

Other therapies include pulmonary rehabilitation, which may improve health-related quality of life and 6-minute walk distance,³⁹ extracorporeal photopheresis,⁴⁰ immunosuppression with calcineurin inhibitors or mycophenolate mofetil,^21,41 and lung transplantation.^42–44 A study with imatinib for the treatment of lung disease in steroid-refractory GVHD has shown promising results, but further validation with larger clinical trials is required.⁴⁵

Case Continued

The patient is diagnosed with BOS and is treated for several months with prednisone 40 mg/day weaned over 3 months. She is started on inhaled corticosteroids, a proton pump inhibitor, and azithromycin 3 times per week, but she has a progressive decline in FEV₁.  She starts pulmonary rehabilitation but continues to functionally decline. Over the next year she develops bilateral pneumothoraces and bilateral cavitary nodules (Figure 1).

• What is causing this decline and the radiographic abnormalities?

Spontaneous air leak syndrome has been described in a little more than 1% of patients undergoing HSCT and has included pneumothorax and mediastinal and subcutaneous emphysema.⁴⁶ It appears that air leak syndrome is more likely to occur in patients with chronic GVHD.⁴⁷ The association between chronic GVHD and air leak syndrome could explain this patient’s recurrent pneumothoraces. The recurrent cavitary nodules are suspicious for infectious etiologies such as nontuberculous mycobacteria, tuberculosis, and fungal infections.

Case Continued

During an episode of pneumothorax, the patient undergoes chest tube placement, pleurodesis, and lung biopsy.  Pathology reveals bronchiolitis obliterans as well as organizing pneumonia (Figure 2). No organisms are seen on acid-fast bacilli or GMS stains.

• What are the other late-onset noninfectious pulmonary complications?

Definitions of other late noninfectious pulmonary complications following HSCT are shown in Table 3.

Interstitial pneumonias may represent COP or may be idiopathic pneumonia syndrome with a later onset or a nonspecific interstitial pneumonia. This syndrome is poorly defined, with a number of differing definitions of the syndrome published in the literature.^50–55

A rare pulmonary complication after HSCT is pulmonary veno-occlusive disease (PVOD). Pulmonary hypertension has been reported after HSCT,⁵⁶ but PVOD is a subset of pulmonary hypertension. It is associated with pleural effusions and volume overload on chest radiography.^57,58 It may present early or late after transplant and is poorly understood.

Besides obstructive and restrictive PFT abnormalities, changes in small airway function⁵⁹ after transplant and loss in diffusing capacity of the lungs for carbon monoxide (Dlco) in the first 5 years after transplant have been reported, although these parameters improve by 10 years after transplant.⁶⁰ There do not appear to be any changes in responsiveness to methacholine.⁶¹ Losses in respiratory muscle strength (PiMax and PeMax after transplant) have been reported.⁶² Lower aerobic exercise capacity (Vo₂max) after pediatric HSCT has also been reported.⁶³

Case Conclusion

The patient’s lung function continues to worsen, but no infectious etiologies are discovered. Ultimately, she dies of respiratory failure caused by progressive bronchiolitis obliterans.

Conclusion

Late pulmonary complications occur frequently in patients who have undergone HSCT. These complications can be classified as infectious versus noninfectious etiologies. Late-onset complications are more common in allogeneic transplantations because they are associated with chronic GVHD. These complications can be manifestations of pulmonary GHVD or can be infectious complications associated with prolonged immunosuppression. Appropriate monitoring for the development of BOS is essential. Early and aggressive treatment of respiratory infections and diagnostic bronchoscopy with BAL can help elucidate most infectious causes. Still, diagnostic challenges remain and multiple causes of respiratory deterioration can be present concurrently in the post-HSCT patient. Steroid therapy remains the mainstay treatment for most noninfectious pulmonary complications and should be strongly considered once infection is effectively ruled out.