Alexander M. Castellino, PhD

The investigational drug asciminib (being developed by Novartis) may become the new kid on the block for the treatment of chronic phase chronic myeloid leukemia (CMP-CP) for patients who have relapsed on or are refractory to at least two prior tyrosine kinase inhibitors (TKIs).

New results from the ASCEMBL study (NCT03106779) show that patients who received asciminib, which works differently from currently approved therapies for CML-CP, achieved better responses, compared with bosutinib (Bosulif) as third-line therapy.

“The ASCEMBL study opens a new chapter for CML, proving comparatively superior efficacy and excellent safety for a new class of ABL inhibitors,” coinvestigator Michael J. Mauro, MD, from Memorial Sloan Kettering Cancer Center, New York, said in an interview.

The trial was presented as a late-breaking abstract at the annual meeting of the American Society of Hematology.

Asciminib is a first-of-a-kind STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that works differently from currently approved TKIs, which are adenosine triphosphate (ATP)-–competitive ABL inhibitors.

Five TKIs have been approved by the Food and Drug Administration to treat CML: imatinib (Gleevec; generics), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib, and ponatinib (Iclusig).

All of them inhibit BCR/ABL tyrosine kinase by binding to the ATP-binding pocket.

Most patients with TKI resistant disease develop mutations in the ATP-binding pocket, explained Michael Jay Styler, MD, associate professor at Fox Chase–Temple University Hospital bone marrow transplant program, Fox Chase Cancer Center, Philadelphia.

By inactivating the protein through binding outside the ATP site, asciminib is a novel BCR-ABL inhibitor and may be a superior alternative to further traditional TKIs. “This agent promises to be an important addition to our treatment armamentarium for CML,” Dr. Styler said in an interview.

Another expert agreed. “Although we have many excellent therapies for CML, having a new medication that targets BCR-ABL in a novel way is still welcome to help us better care for CML patients,” Gabriela S. Hobbs, MD, said in an interview. Dr. Hobbs is the clinical director of leukemia services at Boston’s Mass General Cancer Center.

Patients in this study had previously been receiving at least two different types of TKIs. “The responses looked very encouraging for this group of heavily pretreated patients. Although CML patients do very well on current therapies, those that don’t get a response with TKI remain a difficult clinical challenge,” Dr. Hobbs said.

“This is the first study comparing asciminib to a TKI directly (in this case bosutinib) and it showed safety as well as preliminary evidence of efficacy. I look forward to seeing additional studies with this promising drug and to have a new drug to add to the CML arsenal,” she added.
 

Identifying patients who will benefit from asciminib

Patients with CML are currently sequenced through more than one second-generation TKI, Dr. Mauro commented. “If imatinib and a second-generation TKI have not served a patient well, only bosutinib has been studied in the third line and comparatively in the ASCEMBL study.” Asciminib was shown to be superior and could offer a clear alternative to ponatinib, which would be the other choice and is typically given even later after sequencing all other available options.

Dr. Hobbs agreed. “This is a challenging group of patients to manage as their options are limited. Ponatinib is often the drug of choice in these scenarios, as well as bone marrow transplant.”

Asciminib is not approved yet, but both Dr. Mauro and Dr. Hobbs are hopeful it will be by early next year, and that initial approval is likely in patients with CML-CP after several (two or three) lines of therapy. They also agreed that it may be effective (alone or in combination) in treating patients with T315I-mutation CML, which is a particularly challenging disease.

Senior study author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II in Jena, Germany, who presented the data at the meeting, noted new trials to test the efficacy of asciminib alone or in combination in earlier lines of therapy are ongoing and include the investigator-initiated FASCINATION study (first-line asciminib in combination) in Germany (NCT03906292).
 

ASCEMBL study details

ASCEMBL is a phase 3 study in which patients with CML who had received at least two previous TKIs were randomized to asciminib (n = 157) 40 mg twice daily or bosutinib (n = 76) 500 mg once daily. In a protocol amendment, patients with documented failure on bosutinib were allowed to switch to asciminib.

The main reason for discontinuing the last TKI therapy was lack of efficacy in approximately two-thirds of patients. More patients in the asciminib than the bosutinib group received two prior lines of therapy (52% vs. 40%); the others had received three or more prior lines of therapy.

Median follow-up for the data cutoff was 14.9 months.

Dr. Hochhaus reported that treatment discontinuation was lower in patients receiving asciminib than bosutinib (38% vs. 70%) and was mostly due to lack of efficacy (21% vs. 32%) or adverse events (5% vs. 21%).

The study met its primary endpoint: major molecular response (MMR) was approximately twice as high with asciminib than bosutinib at 24 weeks (25.5% vs. 13.2%; P = .029). Treatment effect for MMR was 12.2%. Median duration of exposure to asciminib was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.

“Consistent treatment effect was seen across all subgroups of patients, and MMR rates were consistently high for patients on asciminib across all prior lines of therapy,” Dr. Hochhaus reported.

The probability of achieving MMR at 24 weeks was higher for patients receiving asciminib (25% vs. 11.9%) and started at week 12, he noted. Complete cytogenetic response was also higher for patients receiving asciminib (40.8% vs. 24.2%).

The occurrence of grade 3 or higher adverse events was lower with asciminib than bosutinib (51% vs. 61%). Thrombocytopenia and neutropenia were more common with asciminib and gastrointestinal events were more common with bosutinib. Arterial occlusion events were reported in five patients receiving asciminib and one patient receiving bosutinib. Most of these patients had prior exposure to imatinib, nilotinib, and/or dasatinib.

Dr. Mauro, a coinvestigator of the phase 3 study, also treated patients with the drug in the phase 1 study. “I feel asciminib has proven to be very well tolerated, with rare to absent cases of intolerance,” he said. Cardiovascular and cardiopulmonary adverse events are exceedingly rare as well.

Longer follow-up of the ASCEMBL study and continued follow-up of the myriad of groups from the phase 1 trial (T315I-positive patients treated with higher-dose asciminib, combination therapy with imatinib/nilotinib/dasatinib plus asciminib, and others) will be essential to settle any questions regarding selective adverse events of interest such as vascular occlusion, Dr. Mauro noted.

Dr. Hochhaus has reported receiving research funding from Novartis, Incyte, Pfizer, and Bristol-Myers Squibb. Dr. Hobbs has reported serving on advisory boards for Novartis. Dr. Mauro has reported financial relationships with Bristol-Myers Squibb, Novartis, Takeda, Pfizer, and Sun Pharma/SPARC.

A version of this article first appeared on Medscape.com.

The investigational drug asciminib (being developed by Novartis) may become the new kid on the block for the treatment of chronic phase chronic myeloid leukemia (CMP-CP) for patients who have relapsed on or are refractory to at least two prior tyrosine kinase inhibitors (TKIs).

New results from the ASCEMBL study (NCT03106779) show that patients who received asciminib, which works differently from currently approved therapies for CML-CP, achieved better responses, compared with bosutinib (Bosulif) as third-line therapy.

“The ASCEMBL study opens a new chapter for CML, proving comparatively superior efficacy and excellent safety for a new class of ABL inhibitors,” coinvestigator Michael J. Mauro, MD, from Memorial Sloan Kettering Cancer Center, New York, said in an interview.

The trial was presented as a late-breaking abstract at the annual meeting of the American Society of Hematology.

Asciminib is a first-of-a-kind STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that works differently from currently approved TKIs, which are adenosine triphosphate (ATP)-–competitive ABL inhibitors.

Five TKIs have been approved by the Food and Drug Administration to treat CML: imatinib (Gleevec; generics), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib, and ponatinib (Iclusig).

All of them inhibit BCR/ABL tyrosine kinase by binding to the ATP-binding pocket.

Most patients with TKI resistant disease develop mutations in the ATP-binding pocket, explained Michael Jay Styler, MD, associate professor at Fox Chase–Temple University Hospital bone marrow transplant program, Fox Chase Cancer Center, Philadelphia.

By inactivating the protein through binding outside the ATP site, asciminib is a novel BCR-ABL inhibitor and may be a superior alternative to further traditional TKIs. “This agent promises to be an important addition to our treatment armamentarium for CML,” Dr. Styler said in an interview.

Another expert agreed. “Although we have many excellent therapies for CML, having a new medication that targets BCR-ABL in a novel way is still welcome to help us better care for CML patients,” Gabriela S. Hobbs, MD, said in an interview. Dr. Hobbs is the clinical director of leukemia services at Boston’s Mass General Cancer Center.

Patients in this study had previously been receiving at least two different types of TKIs. “The responses looked very encouraging for this group of heavily pretreated patients. Although CML patients do very well on current therapies, those that don’t get a response with TKI remain a difficult clinical challenge,” Dr. Hobbs said.

“This is the first study comparing asciminib to a TKI directly (in this case bosutinib) and it showed safety as well as preliminary evidence of efficacy. I look forward to seeing additional studies with this promising drug and to have a new drug to add to the CML arsenal,” she added.
 

Identifying patients who will benefit from asciminib

Patients with CML are currently sequenced through more than one second-generation TKI, Dr. Mauro commented. “If imatinib and a second-generation TKI have not served a patient well, only bosutinib has been studied in the third line and comparatively in the ASCEMBL study.” Asciminib was shown to be superior and could offer a clear alternative to ponatinib, which would be the other choice and is typically given even later after sequencing all other available options.

Dr. Hobbs agreed. “This is a challenging group of patients to manage as their options are limited. Ponatinib is often the drug of choice in these scenarios, as well as bone marrow transplant.”

Asciminib is not approved yet, but both Dr. Mauro and Dr. Hobbs are hopeful it will be by early next year, and that initial approval is likely in patients with CML-CP after several (two or three) lines of therapy. They also agreed that it may be effective (alone or in combination) in treating patients with T315I-mutation CML, which is a particularly challenging disease.

Senior study author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II in Jena, Germany, who presented the data at the meeting, noted new trials to test the efficacy of asciminib alone or in combination in earlier lines of therapy are ongoing and include the investigator-initiated FASCINATION study (first-line asciminib in combination) in Germany (NCT03906292).
 

ASCEMBL study details

ASCEMBL is a phase 3 study in which patients with CML who had received at least two previous TKIs were randomized to asciminib (n = 157) 40 mg twice daily or bosutinib (n = 76) 500 mg once daily. In a protocol amendment, patients with documented failure on bosutinib were allowed to switch to asciminib.

The main reason for discontinuing the last TKI therapy was lack of efficacy in approximately two-thirds of patients. More patients in the asciminib than the bosutinib group received two prior lines of therapy (52% vs. 40%); the others had received three or more prior lines of therapy.

Median follow-up for the data cutoff was 14.9 months.

Dr. Hochhaus reported that treatment discontinuation was lower in patients receiving asciminib than bosutinib (38% vs. 70%) and was mostly due to lack of efficacy (21% vs. 32%) or adverse events (5% vs. 21%).

The study met its primary endpoint: major molecular response (MMR) was approximately twice as high with asciminib than bosutinib at 24 weeks (25.5% vs. 13.2%; P = .029). Treatment effect for MMR was 12.2%. Median duration of exposure to asciminib was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.

“Consistent treatment effect was seen across all subgroups of patients, and MMR rates were consistently high for patients on asciminib across all prior lines of therapy,” Dr. Hochhaus reported.

The probability of achieving MMR at 24 weeks was higher for patients receiving asciminib (25% vs. 11.9%) and started at week 12, he noted. Complete cytogenetic response was also higher for patients receiving asciminib (40.8% vs. 24.2%).

The occurrence of grade 3 or higher adverse events was lower with asciminib than bosutinib (51% vs. 61%). Thrombocytopenia and neutropenia were more common with asciminib and gastrointestinal events were more common with bosutinib. Arterial occlusion events were reported in five patients receiving asciminib and one patient receiving bosutinib. Most of these patients had prior exposure to imatinib, nilotinib, and/or dasatinib.

Dr. Mauro, a coinvestigator of the phase 3 study, also treated patients with the drug in the phase 1 study. “I feel asciminib has proven to be very well tolerated, with rare to absent cases of intolerance,” he said. Cardiovascular and cardiopulmonary adverse events are exceedingly rare as well.

Longer follow-up of the ASCEMBL study and continued follow-up of the myriad of groups from the phase 1 trial (T315I-positive patients treated with higher-dose asciminib, combination therapy with imatinib/nilotinib/dasatinib plus asciminib, and others) will be essential to settle any questions regarding selective adverse events of interest such as vascular occlusion, Dr. Mauro noted.

Dr. Hochhaus has reported receiving research funding from Novartis, Incyte, Pfizer, and Bristol-Myers Squibb. Dr. Hobbs has reported serving on advisory boards for Novartis. Dr. Mauro has reported financial relationships with Bristol-Myers Squibb, Novartis, Takeda, Pfizer, and Sun Pharma/SPARC.

A version of this article first appeared on Medscape.com.

The investigational drug asciminib (being developed by Novartis) may become the new kid on the block for the treatment of chronic phase chronic myeloid leukemia (CMP-CP) for patients who have relapsed on or are refractory to at least two prior tyrosine kinase inhibitors (TKIs).

New results from the ASCEMBL study (NCT03106779) show that patients who received asciminib, which works differently from currently approved therapies for CML-CP, achieved better responses, compared with bosutinib (Bosulif) as third-line therapy.

“The ASCEMBL study opens a new chapter for CML, proving comparatively superior efficacy and excellent safety for a new class of ABL inhibitors,” coinvestigator Michael J. Mauro, MD, from Memorial Sloan Kettering Cancer Center, New York, said in an interview.

The trial was presented as a late-breaking abstract at the annual meeting of the American Society of Hematology.

Asciminib is a first-of-a-kind STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor that works differently from currently approved TKIs, which are adenosine triphosphate (ATP)-–competitive ABL inhibitors.

Five TKIs have been approved by the Food and Drug Administration to treat CML: imatinib (Gleevec; generics), nilotinib (Tasigna), dasatinib (Sprycel), bosutinib, and ponatinib (Iclusig).

All of them inhibit BCR/ABL tyrosine kinase by binding to the ATP-binding pocket.

Most patients with TKI resistant disease develop mutations in the ATP-binding pocket, explained Michael Jay Styler, MD, associate professor at Fox Chase–Temple University Hospital bone marrow transplant program, Fox Chase Cancer Center, Philadelphia.

By inactivating the protein through binding outside the ATP site, asciminib is a novel BCR-ABL inhibitor and may be a superior alternative to further traditional TKIs. “This agent promises to be an important addition to our treatment armamentarium for CML,” Dr. Styler said in an interview.

Another expert agreed. “Although we have many excellent therapies for CML, having a new medication that targets BCR-ABL in a novel way is still welcome to help us better care for CML patients,” Gabriela S. Hobbs, MD, said in an interview. Dr. Hobbs is the clinical director of leukemia services at Boston’s Mass General Cancer Center.

Patients in this study had previously been receiving at least two different types of TKIs. “The responses looked very encouraging for this group of heavily pretreated patients. Although CML patients do very well on current therapies, those that don’t get a response with TKI remain a difficult clinical challenge,” Dr. Hobbs said.

“This is the first study comparing asciminib to a TKI directly (in this case bosutinib) and it showed safety as well as preliminary evidence of efficacy. I look forward to seeing additional studies with this promising drug and to have a new drug to add to the CML arsenal,” she added.
 

Identifying patients who will benefit from asciminib

Patients with CML are currently sequenced through more than one second-generation TKI, Dr. Mauro commented. “If imatinib and a second-generation TKI have not served a patient well, only bosutinib has been studied in the third line and comparatively in the ASCEMBL study.” Asciminib was shown to be superior and could offer a clear alternative to ponatinib, which would be the other choice and is typically given even later after sequencing all other available options.

Dr. Hobbs agreed. “This is a challenging group of patients to manage as their options are limited. Ponatinib is often the drug of choice in these scenarios, as well as bone marrow transplant.”

Asciminib is not approved yet, but both Dr. Mauro and Dr. Hobbs are hopeful it will be by early next year, and that initial approval is likely in patients with CML-CP after several (two or three) lines of therapy. They also agreed that it may be effective (alone or in combination) in treating patients with T315I-mutation CML, which is a particularly challenging disease.

Senior study author Andreas Hochhaus, MD, of the Klinik für Innere Medizin II in Jena, Germany, who presented the data at the meeting, noted new trials to test the efficacy of asciminib alone or in combination in earlier lines of therapy are ongoing and include the investigator-initiated FASCINATION study (first-line asciminib in combination) in Germany (NCT03906292).
 

ASCEMBL study details

ASCEMBL is a phase 3 study in which patients with CML who had received at least two previous TKIs were randomized to asciminib (n = 157) 40 mg twice daily or bosutinib (n = 76) 500 mg once daily. In a protocol amendment, patients with documented failure on bosutinib were allowed to switch to asciminib.

The main reason for discontinuing the last TKI therapy was lack of efficacy in approximately two-thirds of patients. More patients in the asciminib than the bosutinib group received two prior lines of therapy (52% vs. 40%); the others had received three or more prior lines of therapy.

Median follow-up for the data cutoff was 14.9 months.

Dr. Hochhaus reported that treatment discontinuation was lower in patients receiving asciminib than bosutinib (38% vs. 70%) and was mostly due to lack of efficacy (21% vs. 32%) or adverse events (5% vs. 21%).

The study met its primary endpoint: major molecular response (MMR) was approximately twice as high with asciminib than bosutinib at 24 weeks (25.5% vs. 13.2%; P = .029). Treatment effect for MMR was 12.2%. Median duration of exposure to asciminib was 43.4 weeks for asciminib and 29.2 weeks for bosutinib.

“Consistent treatment effect was seen across all subgroups of patients, and MMR rates were consistently high for patients on asciminib across all prior lines of therapy,” Dr. Hochhaus reported.

The probability of achieving MMR at 24 weeks was higher for patients receiving asciminib (25% vs. 11.9%) and started at week 12, he noted. Complete cytogenetic response was also higher for patients receiving asciminib (40.8% vs. 24.2%).

The occurrence of grade 3 or higher adverse events was lower with asciminib than bosutinib (51% vs. 61%). Thrombocytopenia and neutropenia were more common with asciminib and gastrointestinal events were more common with bosutinib. Arterial occlusion events were reported in five patients receiving asciminib and one patient receiving bosutinib. Most of these patients had prior exposure to imatinib, nilotinib, and/or dasatinib.

Dr. Mauro, a coinvestigator of the phase 3 study, also treated patients with the drug in the phase 1 study. “I feel asciminib has proven to be very well tolerated, with rare to absent cases of intolerance,” he said. Cardiovascular and cardiopulmonary adverse events are exceedingly rare as well.

Longer follow-up of the ASCEMBL study and continued follow-up of the myriad of groups from the phase 1 trial (T315I-positive patients treated with higher-dose asciminib, combination therapy with imatinib/nilotinib/dasatinib plus asciminib, and others) will be essential to settle any questions regarding selective adverse events of interest such as vascular occlusion, Dr. Mauro noted.

Dr. Hochhaus has reported receiving research funding from Novartis, Incyte, Pfizer, and Bristol-Myers Squibb. Dr. Hobbs has reported serving on advisory boards for Novartis. Dr. Mauro has reported financial relationships with Bristol-Myers Squibb, Novartis, Takeda, Pfizer, and Sun Pharma/SPARC.

A version of this article first appeared on Medscape.com.

Data from the Apollo study provide proof for the subcutaneous administration (SC) of daratumumab (Darzalex Faspro) in combination with pomalidomide (Pomalyst) and dexamethasone (Pd) for patients with relapsed or refractory multiple myeloma (RRMM).

The SC formulation of daratumumab (with hyaluronidase) was approved in the United States in May, and is administered by injection into the abdomen over 3-5 minutes. Previously the drug was available only as an intravenous infusion.

“The appeal of subcutaneous daratumumab is the 5 minutes it needs for administering, cutting down considerable on ‘chair/clinic’ time. Intravenous daratumumab is given over several hours,” said Joseph Mikhael, MD, MEd, chief medical officer of the International Myeloma Foundation. He also highlighted the low rates of infusion reactions seen with the subcutaneous daratumumab triplet.

“In the COVID era the subcutaneous route may be the way to go,” he said in an interview.

“This is an effective combination with a predictable safety profile that allows for the use of SC daratumumab along with oral pomalidomide and dexamethasone for patients who have received at least one prior line of therapy that included lenalidomide [Revlimid] and a proteasome inhibitor,” commented lead author Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens.

The triplet combination was associated with a 37% reduced risk for progression or death, compared with the two-drug combination of pomalidomide and dexamethasone.

He presented the results from the Apollo trial at the annual meeting of the American Society of Hematology.
 

Treatment landscape of RRMM

Dr. Mikhael, who is also professor in the applied cancer research and drug discovery division at the Translational Genomics Research Institute, Phoenix, provided his insights into Apollo as well as how this triplet fits into the treatment landscape of RRMM.

Daratumumab is approved for use in both RRMM and newly diagnosed MM, either alone or in combination with standard-of-care regimens. The drug already has eight specific indications for the intravenous formulation, and five indications for the SC formulation of daratumumab, Dr. Mikhael noted. The Apollo study “will likely provide the subcutaneous approval for the daratumumab triplet in MM.”

According to Dr. Mikhael, the triplet of daratumumab with pomalidomide and dexamethasone is the most commonly used combination at first relapse, and this phase 3 study provides confirmatory evidence for its initial approval. The initial approval for intravenous daratumumab and Pd was based on a phase 1b study, he noted.

“The Apollo study is the first randomized trial comparing the triplet of D-Pd to Pd,” Noopur Raje, MD, of the Massachusetts General Hospital, Boston, said in an interview. She explained that the majority of patients included in Apollo were refractory to lenalidomide, which is the patient population typically seen at the time of first relapse. “This regimen will be adopted at either first or second relapse in the majority of patients,” Dr. Raje said.

“In keeping with strategy in MM, we use the best triplet first and do not save the best for last,” Dr. Mikhael said. The triplet of the proteasome inhibitor bortezomib (Velcade), lenalidomide, and dexamethasone is used in first-line MM. “Most patients meet the criteria for using D-Pd at first relapse,” he added, noting that all patients in the study have received a proteasome inhibitor and lenalidomide as first-line therapy and had relapsed with or were refractory to these agents.

“The short administration time and significantly low rates of infusion-site reactions are two important considerations for using this triplet with the subcutaneous formulation of daratumumab [at first relapse],” he said.

In the treatment landscape of MM, the triplet of isatuximab (Sarclisa), pomalidomide, and dexamethasone has recently been approved for RRMM based on data from the ICARIA study. Isatuximab and daratumumab are both CD38-directed antibodies. Dr. Mikhael pointed out that the datasets from ICARIA and Apollo with respect to progression-free survival (PFS) and hazard ratios overlapped and were remarkably similar. However, daratumumab now has an advantage in being available as an SC formulation. 

The landscape of MM treatment has been changing rapidly in recent years, and more changes may be afoot. Dr. Mikhael suggested that the quartet of daratumumab, bortezomib, lenalidomide, and dexamethasone is likely to move into the first-line setting for MM based on data from the GRIFFIN study (trial update in Abstract 3243), and then the choice of drugs to use in first relapse would also change.
 

Apollo study details

Apollo was an open-label, phase 3 study that randomly assigned patients with RRMM to receive SC daratumumab in combination with pomalidomide and low-dose dexamethasone (D-Pd; n = 151) or the two-drug combination of Pd (n = 153).

Approximately 80% of the patients were refractory to lenalidomide and half were refractory to a proteasome inhibitor.

Median duration of SC daratumumab administration was 5 minutes. Median duration of study treatment was longer for patients on D-Pd (11.5 months vs. 6.6 months for Pd).

For the primary endpoint, at a median follow up of 16.9 months, median PFS was 12.4 months for patients receiving D-Pd and 6.9 months for those receiving Pd. One-year PFS was 52% for patients receiving the triplet combination and 35% for those receiving Pd. Treatment effect was generally consistent across subgroups examined, Dr. Dimopoulos reported.

Depth of response was significantly higher for patients on D-Pd. Stringent complete remission or CR was seen in 25% of patients on D-Pd versus 4% on Pd. Overall response rate was 69% for patients on D-Pd and 45% for patients on Pd alone (P < .0001). Minimal residual disease negativity was more than four times higher with D-Pd (9% vs. 2% for Pd; P = .0102).

The safety profile of D-Pd was consistent with the known safety profile of SC daratumumab and Pd. Infusion-site reactions were grade 1-2 and occurred in 5% of patients; in addition, only grade 1 injection-site reactions were seen and occurred in 2% of patients. The most serious treatment-emergent adverse events in patients on D-Pd were pneumonia (15% vs. 8% for Pd) and lower respiratory tract infection (12% vs. 9% for Pd). Incidence of secondary primary malignancy was 2% for each group.
 

Apollo results were ‘no surprise’

“These results are of no surprise and further support the current practice of using a three-drug combination in the relapsed setting,” Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, said in an interview.

Although Dr. Fung agreed that the triplet of a proteasome inhibitor, an immunomodulating drug such as lenalidomide, and the steroid dexamethasone is becoming the standard of care for newly diagnosed MM, D-Pd should be considered an excellent option for patients who have limited choices in the relapsed/refractory setting.

However, he said that the median PFS of 12.4 months for patients receiving D-Pd after a median of two prior regimens is not satisfactory.

“The impact on the natural history of the disease will be limited and the duration of responses decline with each treatment regimen, and the true impact on the disease will be an effective frontline strategy.” Dr. Fung said. “This will not be a practice-changing trial. We need to find out which three-drug regimen works best and what biomarkers can predict the response to individual regimen.”

Dr. Dimopoulos reported receiving honoraria from Beigene, Bristol-Myers Squibb, Amgen, Takeda, Celgene, and Janssen. Dr. Mikhael reported receiving honoraria from Amgen, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, Takeda; consulting with Celgene; and receiving research funding from Celgene and Sanofi. Dr. Fung is on the speakers’ bureau of Apollo and receives honoraria from Jansen Oncology and Celgene/Bristol-Myers Squibb. Dr. Raje is a consultant for Bristol-Myers Squibb and Janssen.  

A version of this article originally appeared on Medscape.com.

Data from the Apollo study provide proof for the subcutaneous administration (SC) of daratumumab (Darzalex Faspro) in combination with pomalidomide (Pomalyst) and dexamethasone (Pd) for patients with relapsed or refractory multiple myeloma (RRMM).

The SC formulation of daratumumab (with hyaluronidase) was approved in the United States in May, and is administered by injection into the abdomen over 3-5 minutes. Previously the drug was available only as an intravenous infusion.

“The appeal of subcutaneous daratumumab is the 5 minutes it needs for administering, cutting down considerable on ‘chair/clinic’ time. Intravenous daratumumab is given over several hours,” said Joseph Mikhael, MD, MEd, chief medical officer of the International Myeloma Foundation. He also highlighted the low rates of infusion reactions seen with the subcutaneous daratumumab triplet.

“In the COVID era the subcutaneous route may be the way to go,” he said in an interview.

“This is an effective combination with a predictable safety profile that allows for the use of SC daratumumab along with oral pomalidomide and dexamethasone for patients who have received at least one prior line of therapy that included lenalidomide [Revlimid] and a proteasome inhibitor,” commented lead author Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens.

The triplet combination was associated with a 37% reduced risk for progression or death, compared with the two-drug combination of pomalidomide and dexamethasone.

He presented the results from the Apollo trial at the annual meeting of the American Society of Hematology.
 

Treatment landscape of RRMM

Dr. Mikhael, who is also professor in the applied cancer research and drug discovery division at the Translational Genomics Research Institute, Phoenix, provided his insights into Apollo as well as how this triplet fits into the treatment landscape of RRMM.

Daratumumab is approved for use in both RRMM and newly diagnosed MM, either alone or in combination with standard-of-care regimens. The drug already has eight specific indications for the intravenous formulation, and five indications for the SC formulation of daratumumab, Dr. Mikhael noted. The Apollo study “will likely provide the subcutaneous approval for the daratumumab triplet in MM.”

According to Dr. Mikhael, the triplet of daratumumab with pomalidomide and dexamethasone is the most commonly used combination at first relapse, and this phase 3 study provides confirmatory evidence for its initial approval. The initial approval for intravenous daratumumab and Pd was based on a phase 1b study, he noted.

“The Apollo study is the first randomized trial comparing the triplet of D-Pd to Pd,” Noopur Raje, MD, of the Massachusetts General Hospital, Boston, said in an interview. She explained that the majority of patients included in Apollo were refractory to lenalidomide, which is the patient population typically seen at the time of first relapse. “This regimen will be adopted at either first or second relapse in the majority of patients,” Dr. Raje said.

“In keeping with strategy in MM, we use the best triplet first and do not save the best for last,” Dr. Mikhael said. The triplet of the proteasome inhibitor bortezomib (Velcade), lenalidomide, and dexamethasone is used in first-line MM. “Most patients meet the criteria for using D-Pd at first relapse,” he added, noting that all patients in the study have received a proteasome inhibitor and lenalidomide as first-line therapy and had relapsed with or were refractory to these agents.

“The short administration time and significantly low rates of infusion-site reactions are two important considerations for using this triplet with the subcutaneous formulation of daratumumab [at first relapse],” he said.

In the treatment landscape of MM, the triplet of isatuximab (Sarclisa), pomalidomide, and dexamethasone has recently been approved for RRMM based on data from the ICARIA study. Isatuximab and daratumumab are both CD38-directed antibodies. Dr. Mikhael pointed out that the datasets from ICARIA and Apollo with respect to progression-free survival (PFS) and hazard ratios overlapped and were remarkably similar. However, daratumumab now has an advantage in being available as an SC formulation. 

The landscape of MM treatment has been changing rapidly in recent years, and more changes may be afoot. Dr. Mikhael suggested that the quartet of daratumumab, bortezomib, lenalidomide, and dexamethasone is likely to move into the first-line setting for MM based on data from the GRIFFIN study (trial update in Abstract 3243), and then the choice of drugs to use in first relapse would also change.
 

Apollo study details

Apollo was an open-label, phase 3 study that randomly assigned patients with RRMM to receive SC daratumumab in combination with pomalidomide and low-dose dexamethasone (D-Pd; n = 151) or the two-drug combination of Pd (n = 153).

Approximately 80% of the patients were refractory to lenalidomide and half were refractory to a proteasome inhibitor.

Median duration of SC daratumumab administration was 5 minutes. Median duration of study treatment was longer for patients on D-Pd (11.5 months vs. 6.6 months for Pd).

For the primary endpoint, at a median follow up of 16.9 months, median PFS was 12.4 months for patients receiving D-Pd and 6.9 months for those receiving Pd. One-year PFS was 52% for patients receiving the triplet combination and 35% for those receiving Pd. Treatment effect was generally consistent across subgroups examined, Dr. Dimopoulos reported.

Depth of response was significantly higher for patients on D-Pd. Stringent complete remission or CR was seen in 25% of patients on D-Pd versus 4% on Pd. Overall response rate was 69% for patients on D-Pd and 45% for patients on Pd alone (P < .0001). Minimal residual disease negativity was more than four times higher with D-Pd (9% vs. 2% for Pd; P = .0102).

The safety profile of D-Pd was consistent with the known safety profile of SC daratumumab and Pd. Infusion-site reactions were grade 1-2 and occurred in 5% of patients; in addition, only grade 1 injection-site reactions were seen and occurred in 2% of patients. The most serious treatment-emergent adverse events in patients on D-Pd were pneumonia (15% vs. 8% for Pd) and lower respiratory tract infection (12% vs. 9% for Pd). Incidence of secondary primary malignancy was 2% for each group.
 

Apollo results were ‘no surprise’

“These results are of no surprise and further support the current practice of using a three-drug combination in the relapsed setting,” Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, said in an interview.

Although Dr. Fung agreed that the triplet of a proteasome inhibitor, an immunomodulating drug such as lenalidomide, and the steroid dexamethasone is becoming the standard of care for newly diagnosed MM, D-Pd should be considered an excellent option for patients who have limited choices in the relapsed/refractory setting.

However, he said that the median PFS of 12.4 months for patients receiving D-Pd after a median of two prior regimens is not satisfactory.

“The impact on the natural history of the disease will be limited and the duration of responses decline with each treatment regimen, and the true impact on the disease will be an effective frontline strategy.” Dr. Fung said. “This will not be a practice-changing trial. We need to find out which three-drug regimen works best and what biomarkers can predict the response to individual regimen.”

Dr. Dimopoulos reported receiving honoraria from Beigene, Bristol-Myers Squibb, Amgen, Takeda, Celgene, and Janssen. Dr. Mikhael reported receiving honoraria from Amgen, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, Takeda; consulting with Celgene; and receiving research funding from Celgene and Sanofi. Dr. Fung is on the speakers’ bureau of Apollo and receives honoraria from Jansen Oncology and Celgene/Bristol-Myers Squibb. Dr. Raje is a consultant for Bristol-Myers Squibb and Janssen.  

A version of this article originally appeared on Medscape.com.

Data from the Apollo study provide proof for the subcutaneous administration (SC) of daratumumab (Darzalex Faspro) in combination with pomalidomide (Pomalyst) and dexamethasone (Pd) for patients with relapsed or refractory multiple myeloma (RRMM).

The SC formulation of daratumumab (with hyaluronidase) was approved in the United States in May, and is administered by injection into the abdomen over 3-5 minutes. Previously the drug was available only as an intravenous infusion.

“The appeal of subcutaneous daratumumab is the 5 minutes it needs for administering, cutting down considerable on ‘chair/clinic’ time. Intravenous daratumumab is given over several hours,” said Joseph Mikhael, MD, MEd, chief medical officer of the International Myeloma Foundation. He also highlighted the low rates of infusion reactions seen with the subcutaneous daratumumab triplet.

“In the COVID era the subcutaneous route may be the way to go,” he said in an interview.

“This is an effective combination with a predictable safety profile that allows for the use of SC daratumumab along with oral pomalidomide and dexamethasone for patients who have received at least one prior line of therapy that included lenalidomide [Revlimid] and a proteasome inhibitor,” commented lead author Meletios A. Dimopoulos, MD, of the National and Kapodistrian University of Athens.

The triplet combination was associated with a 37% reduced risk for progression or death, compared with the two-drug combination of pomalidomide and dexamethasone.

He presented the results from the Apollo trial at the annual meeting of the American Society of Hematology.
 

Treatment landscape of RRMM

Dr. Mikhael, who is also professor in the applied cancer research and drug discovery division at the Translational Genomics Research Institute, Phoenix, provided his insights into Apollo as well as how this triplet fits into the treatment landscape of RRMM.

Daratumumab is approved for use in both RRMM and newly diagnosed MM, either alone or in combination with standard-of-care regimens. The drug already has eight specific indications for the intravenous formulation, and five indications for the SC formulation of daratumumab, Dr. Mikhael noted. The Apollo study “will likely provide the subcutaneous approval for the daratumumab triplet in MM.”

According to Dr. Mikhael, the triplet of daratumumab with pomalidomide and dexamethasone is the most commonly used combination at first relapse, and this phase 3 study provides confirmatory evidence for its initial approval. The initial approval for intravenous daratumumab and Pd was based on a phase 1b study, he noted.

“The Apollo study is the first randomized trial comparing the triplet of D-Pd to Pd,” Noopur Raje, MD, of the Massachusetts General Hospital, Boston, said in an interview. She explained that the majority of patients included in Apollo were refractory to lenalidomide, which is the patient population typically seen at the time of first relapse. “This regimen will be adopted at either first or second relapse in the majority of patients,” Dr. Raje said.

“In keeping with strategy in MM, we use the best triplet first and do not save the best for last,” Dr. Mikhael said. The triplet of the proteasome inhibitor bortezomib (Velcade), lenalidomide, and dexamethasone is used in first-line MM. “Most patients meet the criteria for using D-Pd at first relapse,” he added, noting that all patients in the study have received a proteasome inhibitor and lenalidomide as first-line therapy and had relapsed with or were refractory to these agents.

“The short administration time and significantly low rates of infusion-site reactions are two important considerations for using this triplet with the subcutaneous formulation of daratumumab [at first relapse],” he said.

In the treatment landscape of MM, the triplet of isatuximab (Sarclisa), pomalidomide, and dexamethasone has recently been approved for RRMM based on data from the ICARIA study. Isatuximab and daratumumab are both CD38-directed antibodies. Dr. Mikhael pointed out that the datasets from ICARIA and Apollo with respect to progression-free survival (PFS) and hazard ratios overlapped and were remarkably similar. However, daratumumab now has an advantage in being available as an SC formulation. 

The landscape of MM treatment has been changing rapidly in recent years, and more changes may be afoot. Dr. Mikhael suggested that the quartet of daratumumab, bortezomib, lenalidomide, and dexamethasone is likely to move into the first-line setting for MM based on data from the GRIFFIN study (trial update in Abstract 3243), and then the choice of drugs to use in first relapse would also change.
 

Apollo study details

Apollo was an open-label, phase 3 study that randomly assigned patients with RRMM to receive SC daratumumab in combination with pomalidomide and low-dose dexamethasone (D-Pd; n = 151) or the two-drug combination of Pd (n = 153).

Approximately 80% of the patients were refractory to lenalidomide and half were refractory to a proteasome inhibitor.

Median duration of SC daratumumab administration was 5 minutes. Median duration of study treatment was longer for patients on D-Pd (11.5 months vs. 6.6 months for Pd).

For the primary endpoint, at a median follow up of 16.9 months, median PFS was 12.4 months for patients receiving D-Pd and 6.9 months for those receiving Pd. One-year PFS was 52% for patients receiving the triplet combination and 35% for those receiving Pd. Treatment effect was generally consistent across subgroups examined, Dr. Dimopoulos reported.

Depth of response was significantly higher for patients on D-Pd. Stringent complete remission or CR was seen in 25% of patients on D-Pd versus 4% on Pd. Overall response rate was 69% for patients on D-Pd and 45% for patients on Pd alone (P < .0001). Minimal residual disease negativity was more than four times higher with D-Pd (9% vs. 2% for Pd; P = .0102).

The safety profile of D-Pd was consistent with the known safety profile of SC daratumumab and Pd. Infusion-site reactions were grade 1-2 and occurred in 5% of patients; in addition, only grade 1 injection-site reactions were seen and occurred in 2% of patients. The most serious treatment-emergent adverse events in patients on D-Pd were pneumonia (15% vs. 8% for Pd) and lower respiratory tract infection (12% vs. 9% for Pd). Incidence of secondary primary malignancy was 2% for each group.
 

Apollo results were ‘no surprise’

“These results are of no surprise and further support the current practice of using a three-drug combination in the relapsed setting,” Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, said in an interview.

Although Dr. Fung agreed that the triplet of a proteasome inhibitor, an immunomodulating drug such as lenalidomide, and the steroid dexamethasone is becoming the standard of care for newly diagnosed MM, D-Pd should be considered an excellent option for patients who have limited choices in the relapsed/refractory setting.

However, he said that the median PFS of 12.4 months for patients receiving D-Pd after a median of two prior regimens is not satisfactory.

“The impact on the natural history of the disease will be limited and the duration of responses decline with each treatment regimen, and the true impact on the disease will be an effective frontline strategy.” Dr. Fung said. “This will not be a practice-changing trial. We need to find out which three-drug regimen works best and what biomarkers can predict the response to individual regimen.”

Dr. Dimopoulos reported receiving honoraria from Beigene, Bristol-Myers Squibb, Amgen, Takeda, Celgene, and Janssen. Dr. Mikhael reported receiving honoraria from Amgen, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, Takeda; consulting with Celgene; and receiving research funding from Celgene and Sanofi. Dr. Fung is on the speakers’ bureau of Apollo and receives honoraria from Jansen Oncology and Celgene/Bristol-Myers Squibb. Dr. Raje is a consultant for Bristol-Myers Squibb and Janssen.  

A version of this article originally appeared on Medscape.com.

New results suggest that allogeneic hematopoietic cell transplantation (HCT), which is typically reserved for younger patients, may well be offered to older patients with advanced myelodysplastic syndrome (MDS).

In patients with a median age of 66 years who had received a donor transplant, the overall survival (OS) at 3 years was almost double compared with patients who did not receive a transplant – 47.9% vs. 26.6% for the “no-donor” group.  

The finding comes from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Study 1102 (NCT02016781) presented at the American Society of Hematology (ASH) 2020 virtual meeting.

“This study conclusively solidifies the role of transplantation in older individuals with MDS,” presenter Corey Cutler, MD, MPH, of the Dana-Farber Cancer Center, Boston, said in an interview.

Coauthor Ryotaro Nakamura, MD, of City of Hope, Duarte, Calif., said in an interview that this was the largest and first trial in the United States to determine in a prospective fashion that allogeneic stem cell transplantation offers a significant survival in older patients. “There was more than a 20% benefit in OS in this age group,” he said.

“This is an incredibly important study,” said Andrew Brunner, MD, medical oncologist at the Mass General Cancer Center in Boston, who was approached for comment. He explained that for years early transplant was recommended as important for patients who have higher-risk MDS. “This study validates this in a prospective, pseudo-randomized (donor/no donor) fashion,” he said in an interview.

“[This study] is really a seminal advance in the care of patients with MDS. Transplant should be integrated into the care algorithm, if not already, and we as a community need to build upon this study further,” Dr. Brunner added.

Several experts in addition to the authors hailed the study as practice changing.

Robert A. Brodsky, MD, ASH, director of the division of hematology at Johns Hopkins University, Baltimore, noted that in younger patients bone marrow transplant is the standard of care for aggressive MDS, but a lot of practices do not refer older patients or those with comorbidities for transplant and prefer to give these patients palliative care with hypomethylating agents for fear that the transplant process would be too toxic.

“There has been an institutional bias to do transplant in older patients, but until now there was no randomized clinical trial to show that this is the right choice. Now we have the data,” Dr Brodsky said, predicting that “this study will change the standard of care.”

Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, agreed. “We should congratulate all the investigators and our patients who participated in this study. Reduced intensity allogeneic stem cell transplantation improved disease control and overall survival with similar quality of life.

“I will recommend all patients with intermediate-2 or higher-risk MDS to be evaluated by the transplant team at diagnosis and eligible patients should be considered for a transplant,” Dr. Fung said in an interview.

Immediate impact on clinical practice

Lead author Dr. Cutler suggested that the study results had an immediate impact for changing clinical practice. “Individuals between the ages of 50 and 75 years with intermediate-2 or high-risk MDS who are eligible to undergo reduced-intensity transplantation had superior outcomes if they had a suitable donor for transplantation in comparison with those who did not have a donor,” he said.

Dr. Cutler further explained that many community-based hematologists do not refer their patients for transplantation. In addition, there is a lack of a uniform payer position for transplantation for MDS, he noted. Also, there is a lack of understanding of the cost-effectiveness of transplantation in comparison to nontransplant strategies, he suggested.

“Transplant is curative for MDS,” he emphasized. Most transplant recipients will eventually become transfusion-independent within weeks to months from transplant.

“We do transplants in this age group all the time,” Dr. Cutler noted. He said that academic centers will continue to offer transplants, and suggested that community oncologists encourage referral to transplant centers early in a patient’s disease course to maximize search time and provide patients all potential options for therapy.

Dr. Brunner agreed and noted that there is a need to build capacity for higher transplant volume, and in general physicians should seek ways to expand this treatment option to more patients. “At this time, allogeneic transplant still requires close collaboration with referral centers; that said, more and more we are able to work closely with colleagues in the community to share management, including earlier after the actual transplant,” he said.

He noted that one silver lining of the pandemic in 2020 has been increased use of telemedicine to collaborate. “Ongoing advances may be able to further encourage these virtual connections to enhance the entire patient care experience,” Dr. Brunner said.
 

Reimbursement by CMS for Medicare recipients

Despite the data showing benefit, allogeneic stem cell transplantation is not offered to older individuals with high-risk MDS and is not covered by Medicare in the United States, Dr. Cutler noted in his presentation.

“This study was spurred by the CMS [Centers for Medicare & Medicaid Services] ruling for transplantation in MDS and the story has come full circle,” Aaron T. Gerds, MD, MS, noted at a preconference press briefing. Dr. Gerds is chair of the ASH Committee on Communications and assistant professor at the Cleveland Clinic Taussig Cancer Institute, Cleveland.

Dr. Nakamura explained that in 2010 a CMS decision memo noted that the evidence of a benefit for transplantation in MDS was lacking and Medicare would not cover transplant unless patients were enrolled in a clinical study. That memo outlined criteria that a clinical trial would have to address before it could consider reimbursement for Medicare beneficiaries.

“The BMT CTN Study 1102 was one of two studies that met the criteria set by CMS,” Dr. Nakamura said, noting that the data are being prepared for CMS review.

“This study will likely be the deciding factor for CMS to begin to cover payment for transplantation for MDS,” said Dr. Cutler.

The other study, published earlier this year in JAMA Oncology, showed that outcomes for patients older than ager 65 were similar to those of patients aged 55-65.
 

BMT CTN 1102 study details

Dr. Cutler noted that the study was designed to address the issue of whether transplantation was beneficial to Medicare-aged individuals with high-risk MDS, and the trial had been approved by Medicare.

The multicenter study enrolled patients who were between ages 50 and 75 years and had newly diagnosed MDS of higher risk (International Prognostic Scoring System [IPSS] intermediate-2 or higher) and were candidates for reduced intensity conditioning (RIC) allogeneic HCT.

Patients were enrolled prior to a formal donor search and were initially assigned to the “no donor” group and reassigned to the donor group when a suitable donor (matched sibling or unrelated donor) was identified. Patients underwent RIC HCT according to institution protocol.

Of 384 patients, 260 received RIC HCT and 124 received hypomethylating therapy. Median follow-up was 34.2 months for the donor group and 26.9 months for the no-donor group.

The two arms were well balanced with respect to age (median 66 years), gender, disease risk [two-thirds of the patients had an intermediate-2 and one third had a high-risk MDS], and response to hypomethylating therapy. The majority of subjects in the donor arm had unrelated donors and more than one-third had a high comorbidity score, Dr. Cutler indicated.

At 3 years, absolute improvement in OS was 21.3% in favor of donor-arm subjects. Leukemia-free survival was also higher in the donor group: 35.8% vs. 20.6% for the no-donor group.

Improvement in OS for patients receiving transplants was seen across all patient subtypes, regardless of age, response to hypomethylating therapy, and IPSS score. “Treatment effects were seen in any subgroup, but particularly in subjects above age 65,” Dr. Cutler stressed.

In an as-treated analysis that excluded subjects who died, the treatment effects were even more pronounced, with an absolute improvement in OS of 31.4% (47.4% vs. 16% for the no-donor arm) and improvement in leukemia-free survival of 28.4% (39.3% vs. 10.9% for the no-donor arm).

In 25 patients in the no-donor arm who subsequently went on to receive alternate donor transplant, the 3-year OS and leukemia-free survival was 58.5%, underscoring the potential value of alternate donor transplant, Dr. Cutler noted.

Dr. Nakamura emphasized that the gains in survival benefits were not seen at the expense of quality of life, as preliminary results showed no difference in quality-of-life measures across those who received donor transplants and those who did not.

Dr. Brunner noted that physicians often highlight the toxicities of transplant as a consideration for whether to proceed, and while there are toxicities specific to transplant that should be considered, in this study it is seen that, even early on, survival is improved in those patients who move toward early transplant. “It also underscores the limitations of current nontransplant treatments for MDS – there is much room to improve,” he said.
 

Role for alternate donors

Dr. Cutler noted that the majority of patients in the no-donor group died without transplantation. “We need to establish the role of alternative donor transplantation in this population,” he said. Dr. Nakamura indicated that mismatched donors and haploidentical donors such as family donors and umbilical cord blood may be alternate donor sources; outcomes from published studies show similar results, he said.

However, Dr. Brunner noted that the study looked only at traditional fully matched donors, leaving open some questions about alternative donor options such as haploidentical donors and umbilical cord blood donation.

“Our experience in other areas of transplant would suggest that these donor sources may be as good as traditional fully matched options, when using newer conditioning and prophylaxis regimens,” Dr. Brunner said.

Dr. Cutler added, “With the increased acceptance of alternate transplant modalities, we need to determine the outcomes associated with these in prospective trials.”

“I think a significant consideration here as well is health equity,” Dr. Brunner said. “Donor options vary according to race and ethnicity and we need to be proactive as a community to ensure that all MDS patients have access to a potentially curative option early in their diagnosis.”

Dr. Cutler reports consultancy for Mesoblast, Generon, Medsenic, Jazz, Kadmon, and Incyte. Dr. Nakamura reports relationships with Magenta Therapeutics, Kyowa-Kirin, Alexion, Merck, NapaJen Pharma, Kadmon Corporation, Celgene, and Viracor. Dr. Fung has disclosed no relevant financial relationships. Dr. Brodsky reports receiving funding from and being on the board/advisory committee for Achillion Pharmaceuticals, consults with Alexion Pharmaceuticals, and receives honoraria from UpToDate. Dr. Brunner reports relationships with Biogen, Acceleron Pharma Inc, Celgene/BMS, Forty Seven Inc, Jazz Pharma, Novartis, Takeda, Xcenda, GSK, Janssen, and AstraZeneca.

A version of this article originally appeared on Medscape.com.

New results suggest that allogeneic hematopoietic cell transplantation (HCT), which is typically reserved for younger patients, may well be offered to older patients with advanced myelodysplastic syndrome (MDS).

In patients with a median age of 66 years who had received a donor transplant, the overall survival (OS) at 3 years was almost double compared with patients who did not receive a transplant – 47.9% vs. 26.6% for the “no-donor” group.  

The finding comes from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Study 1102 (NCT02016781) presented at the American Society of Hematology (ASH) 2020 virtual meeting.

“This study conclusively solidifies the role of transplantation in older individuals with MDS,” presenter Corey Cutler, MD, MPH, of the Dana-Farber Cancer Center, Boston, said in an interview.

Coauthor Ryotaro Nakamura, MD, of City of Hope, Duarte, Calif., said in an interview that this was the largest and first trial in the United States to determine in a prospective fashion that allogeneic stem cell transplantation offers a significant survival in older patients. “There was more than a 20% benefit in OS in this age group,” he said.

“This is an incredibly important study,” said Andrew Brunner, MD, medical oncologist at the Mass General Cancer Center in Boston, who was approached for comment. He explained that for years early transplant was recommended as important for patients who have higher-risk MDS. “This study validates this in a prospective, pseudo-randomized (donor/no donor) fashion,” he said in an interview.

“[This study] is really a seminal advance in the care of patients with MDS. Transplant should be integrated into the care algorithm, if not already, and we as a community need to build upon this study further,” Dr. Brunner added.

Several experts in addition to the authors hailed the study as practice changing.

Robert A. Brodsky, MD, ASH, director of the division of hematology at Johns Hopkins University, Baltimore, noted that in younger patients bone marrow transplant is the standard of care for aggressive MDS, but a lot of practices do not refer older patients or those with comorbidities for transplant and prefer to give these patients palliative care with hypomethylating agents for fear that the transplant process would be too toxic.

“There has been an institutional bias to do transplant in older patients, but until now there was no randomized clinical trial to show that this is the right choice. Now we have the data,” Dr Brodsky said, predicting that “this study will change the standard of care.”

Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, agreed. “We should congratulate all the investigators and our patients who participated in this study. Reduced intensity allogeneic stem cell transplantation improved disease control and overall survival with similar quality of life.

“I will recommend all patients with intermediate-2 or higher-risk MDS to be evaluated by the transplant team at diagnosis and eligible patients should be considered for a transplant,” Dr. Fung said in an interview.

Immediate impact on clinical practice

Lead author Dr. Cutler suggested that the study results had an immediate impact for changing clinical practice. “Individuals between the ages of 50 and 75 years with intermediate-2 or high-risk MDS who are eligible to undergo reduced-intensity transplantation had superior outcomes if they had a suitable donor for transplantation in comparison with those who did not have a donor,” he said.

Dr. Cutler further explained that many community-based hematologists do not refer their patients for transplantation. In addition, there is a lack of a uniform payer position for transplantation for MDS, he noted. Also, there is a lack of understanding of the cost-effectiveness of transplantation in comparison to nontransplant strategies, he suggested.

“Transplant is curative for MDS,” he emphasized. Most transplant recipients will eventually become transfusion-independent within weeks to months from transplant.

“We do transplants in this age group all the time,” Dr. Cutler noted. He said that academic centers will continue to offer transplants, and suggested that community oncologists encourage referral to transplant centers early in a patient’s disease course to maximize search time and provide patients all potential options for therapy.

Dr. Brunner agreed and noted that there is a need to build capacity for higher transplant volume, and in general physicians should seek ways to expand this treatment option to more patients. “At this time, allogeneic transplant still requires close collaboration with referral centers; that said, more and more we are able to work closely with colleagues in the community to share management, including earlier after the actual transplant,” he said.

He noted that one silver lining of the pandemic in 2020 has been increased use of telemedicine to collaborate. “Ongoing advances may be able to further encourage these virtual connections to enhance the entire patient care experience,” Dr. Brunner said.
 

Reimbursement by CMS for Medicare recipients

Despite the data showing benefit, allogeneic stem cell transplantation is not offered to older individuals with high-risk MDS and is not covered by Medicare in the United States, Dr. Cutler noted in his presentation.

“This study was spurred by the CMS [Centers for Medicare & Medicaid Services] ruling for transplantation in MDS and the story has come full circle,” Aaron T. Gerds, MD, MS, noted at a preconference press briefing. Dr. Gerds is chair of the ASH Committee on Communications and assistant professor at the Cleveland Clinic Taussig Cancer Institute, Cleveland.

Dr. Nakamura explained that in 2010 a CMS decision memo noted that the evidence of a benefit for transplantation in MDS was lacking and Medicare would not cover transplant unless patients were enrolled in a clinical study. That memo outlined criteria that a clinical trial would have to address before it could consider reimbursement for Medicare beneficiaries.

“The BMT CTN Study 1102 was one of two studies that met the criteria set by CMS,” Dr. Nakamura said, noting that the data are being prepared for CMS review.

“This study will likely be the deciding factor for CMS to begin to cover payment for transplantation for MDS,” said Dr. Cutler.

The other study, published earlier this year in JAMA Oncology, showed that outcomes for patients older than ager 65 were similar to those of patients aged 55-65.
 

BMT CTN 1102 study details

Dr. Cutler noted that the study was designed to address the issue of whether transplantation was beneficial to Medicare-aged individuals with high-risk MDS, and the trial had been approved by Medicare.

The multicenter study enrolled patients who were between ages 50 and 75 years and had newly diagnosed MDS of higher risk (International Prognostic Scoring System [IPSS] intermediate-2 or higher) and were candidates for reduced intensity conditioning (RIC) allogeneic HCT.

Patients were enrolled prior to a formal donor search and were initially assigned to the “no donor” group and reassigned to the donor group when a suitable donor (matched sibling or unrelated donor) was identified. Patients underwent RIC HCT according to institution protocol.

Of 384 patients, 260 received RIC HCT and 124 received hypomethylating therapy. Median follow-up was 34.2 months for the donor group and 26.9 months for the no-donor group.

The two arms were well balanced with respect to age (median 66 years), gender, disease risk [two-thirds of the patients had an intermediate-2 and one third had a high-risk MDS], and response to hypomethylating therapy. The majority of subjects in the donor arm had unrelated donors and more than one-third had a high comorbidity score, Dr. Cutler indicated.

At 3 years, absolute improvement in OS was 21.3% in favor of donor-arm subjects. Leukemia-free survival was also higher in the donor group: 35.8% vs. 20.6% for the no-donor group.

Improvement in OS for patients receiving transplants was seen across all patient subtypes, regardless of age, response to hypomethylating therapy, and IPSS score. “Treatment effects were seen in any subgroup, but particularly in subjects above age 65,” Dr. Cutler stressed.

In an as-treated analysis that excluded subjects who died, the treatment effects were even more pronounced, with an absolute improvement in OS of 31.4% (47.4% vs. 16% for the no-donor arm) and improvement in leukemia-free survival of 28.4% (39.3% vs. 10.9% for the no-donor arm).

In 25 patients in the no-donor arm who subsequently went on to receive alternate donor transplant, the 3-year OS and leukemia-free survival was 58.5%, underscoring the potential value of alternate donor transplant, Dr. Cutler noted.

Dr. Nakamura emphasized that the gains in survival benefits were not seen at the expense of quality of life, as preliminary results showed no difference in quality-of-life measures across those who received donor transplants and those who did not.

Dr. Brunner noted that physicians often highlight the toxicities of transplant as a consideration for whether to proceed, and while there are toxicities specific to transplant that should be considered, in this study it is seen that, even early on, survival is improved in those patients who move toward early transplant. “It also underscores the limitations of current nontransplant treatments for MDS – there is much room to improve,” he said.
 

Role for alternate donors

Dr. Cutler noted that the majority of patients in the no-donor group died without transplantation. “We need to establish the role of alternative donor transplantation in this population,” he said. Dr. Nakamura indicated that mismatched donors and haploidentical donors such as family donors and umbilical cord blood may be alternate donor sources; outcomes from published studies show similar results, he said.

However, Dr. Brunner noted that the study looked only at traditional fully matched donors, leaving open some questions about alternative donor options such as haploidentical donors and umbilical cord blood donation.

“Our experience in other areas of transplant would suggest that these donor sources may be as good as traditional fully matched options, when using newer conditioning and prophylaxis regimens,” Dr. Brunner said.

Dr. Cutler added, “With the increased acceptance of alternate transplant modalities, we need to determine the outcomes associated with these in prospective trials.”

“I think a significant consideration here as well is health equity,” Dr. Brunner said. “Donor options vary according to race and ethnicity and we need to be proactive as a community to ensure that all MDS patients have access to a potentially curative option early in their diagnosis.”

Dr. Cutler reports consultancy for Mesoblast, Generon, Medsenic, Jazz, Kadmon, and Incyte. Dr. Nakamura reports relationships with Magenta Therapeutics, Kyowa-Kirin, Alexion, Merck, NapaJen Pharma, Kadmon Corporation, Celgene, and Viracor. Dr. Fung has disclosed no relevant financial relationships. Dr. Brodsky reports receiving funding from and being on the board/advisory committee for Achillion Pharmaceuticals, consults with Alexion Pharmaceuticals, and receives honoraria from UpToDate. Dr. Brunner reports relationships with Biogen, Acceleron Pharma Inc, Celgene/BMS, Forty Seven Inc, Jazz Pharma, Novartis, Takeda, Xcenda, GSK, Janssen, and AstraZeneca.

A version of this article originally appeared on Medscape.com.

New results suggest that allogeneic hematopoietic cell transplantation (HCT), which is typically reserved for younger patients, may well be offered to older patients with advanced myelodysplastic syndrome (MDS).

In patients with a median age of 66 years who had received a donor transplant, the overall survival (OS) at 3 years was almost double compared with patients who did not receive a transplant – 47.9% vs. 26.6% for the “no-donor” group.  

The finding comes from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Study 1102 (NCT02016781) presented at the American Society of Hematology (ASH) 2020 virtual meeting.

“This study conclusively solidifies the role of transplantation in older individuals with MDS,” presenter Corey Cutler, MD, MPH, of the Dana-Farber Cancer Center, Boston, said in an interview.

Coauthor Ryotaro Nakamura, MD, of City of Hope, Duarte, Calif., said in an interview that this was the largest and first trial in the United States to determine in a prospective fashion that allogeneic stem cell transplantation offers a significant survival in older patients. “There was more than a 20% benefit in OS in this age group,” he said.

“This is an incredibly important study,” said Andrew Brunner, MD, medical oncologist at the Mass General Cancer Center in Boston, who was approached for comment. He explained that for years early transplant was recommended as important for patients who have higher-risk MDS. “This study validates this in a prospective, pseudo-randomized (donor/no donor) fashion,” he said in an interview.

“[This study] is really a seminal advance in the care of patients with MDS. Transplant should be integrated into the care algorithm, if not already, and we as a community need to build upon this study further,” Dr. Brunner added.

Several experts in addition to the authors hailed the study as practice changing.

Robert A. Brodsky, MD, ASH, director of the division of hematology at Johns Hopkins University, Baltimore, noted that in younger patients bone marrow transplant is the standard of care for aggressive MDS, but a lot of practices do not refer older patients or those with comorbidities for transplant and prefer to give these patients palliative care with hypomethylating agents for fear that the transplant process would be too toxic.

“There has been an institutional bias to do transplant in older patients, but until now there was no randomized clinical trial to show that this is the right choice. Now we have the data,” Dr Brodsky said, predicting that “this study will change the standard of care.”

Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase Cancer Center, Philadelphia, agreed. “We should congratulate all the investigators and our patients who participated in this study. Reduced intensity allogeneic stem cell transplantation improved disease control and overall survival with similar quality of life.

“I will recommend all patients with intermediate-2 or higher-risk MDS to be evaluated by the transplant team at diagnosis and eligible patients should be considered for a transplant,” Dr. Fung said in an interview.

Immediate impact on clinical practice

Lead author Dr. Cutler suggested that the study results had an immediate impact for changing clinical practice. “Individuals between the ages of 50 and 75 years with intermediate-2 or high-risk MDS who are eligible to undergo reduced-intensity transplantation had superior outcomes if they had a suitable donor for transplantation in comparison with those who did not have a donor,” he said.

Dr. Cutler further explained that many community-based hematologists do not refer their patients for transplantation. In addition, there is a lack of a uniform payer position for transplantation for MDS, he noted. Also, there is a lack of understanding of the cost-effectiveness of transplantation in comparison to nontransplant strategies, he suggested.

“Transplant is curative for MDS,” he emphasized. Most transplant recipients will eventually become transfusion-independent within weeks to months from transplant.

“We do transplants in this age group all the time,” Dr. Cutler noted. He said that academic centers will continue to offer transplants, and suggested that community oncologists encourage referral to transplant centers early in a patient’s disease course to maximize search time and provide patients all potential options for therapy.

Dr. Brunner agreed and noted that there is a need to build capacity for higher transplant volume, and in general physicians should seek ways to expand this treatment option to more patients. “At this time, allogeneic transplant still requires close collaboration with referral centers; that said, more and more we are able to work closely with colleagues in the community to share management, including earlier after the actual transplant,” he said.

He noted that one silver lining of the pandemic in 2020 has been increased use of telemedicine to collaborate. “Ongoing advances may be able to further encourage these virtual connections to enhance the entire patient care experience,” Dr. Brunner said.
 

Reimbursement by CMS for Medicare recipients

Despite the data showing benefit, allogeneic stem cell transplantation is not offered to older individuals with high-risk MDS and is not covered by Medicare in the United States, Dr. Cutler noted in his presentation.

“This study was spurred by the CMS [Centers for Medicare & Medicaid Services] ruling for transplantation in MDS and the story has come full circle,” Aaron T. Gerds, MD, MS, noted at a preconference press briefing. Dr. Gerds is chair of the ASH Committee on Communications and assistant professor at the Cleveland Clinic Taussig Cancer Institute, Cleveland.

Dr. Nakamura explained that in 2010 a CMS decision memo noted that the evidence of a benefit for transplantation in MDS was lacking and Medicare would not cover transplant unless patients were enrolled in a clinical study. That memo outlined criteria that a clinical trial would have to address before it could consider reimbursement for Medicare beneficiaries.

“The BMT CTN Study 1102 was one of two studies that met the criteria set by CMS,” Dr. Nakamura said, noting that the data are being prepared for CMS review.

“This study will likely be the deciding factor for CMS to begin to cover payment for transplantation for MDS,” said Dr. Cutler.

The other study, published earlier this year in JAMA Oncology, showed that outcomes for patients older than ager 65 were similar to those of patients aged 55-65.
 

BMT CTN 1102 study details

Dr. Cutler noted that the study was designed to address the issue of whether transplantation was beneficial to Medicare-aged individuals with high-risk MDS, and the trial had been approved by Medicare.

The multicenter study enrolled patients who were between ages 50 and 75 years and had newly diagnosed MDS of higher risk (International Prognostic Scoring System [IPSS] intermediate-2 or higher) and were candidates for reduced intensity conditioning (RIC) allogeneic HCT.

Patients were enrolled prior to a formal donor search and were initially assigned to the “no donor” group and reassigned to the donor group when a suitable donor (matched sibling or unrelated donor) was identified. Patients underwent RIC HCT according to institution protocol.

Of 384 patients, 260 received RIC HCT and 124 received hypomethylating therapy. Median follow-up was 34.2 months for the donor group and 26.9 months for the no-donor group.

The two arms were well balanced with respect to age (median 66 years), gender, disease risk [two-thirds of the patients had an intermediate-2 and one third had a high-risk MDS], and response to hypomethylating therapy. The majority of subjects in the donor arm had unrelated donors and more than one-third had a high comorbidity score, Dr. Cutler indicated.

At 3 years, absolute improvement in OS was 21.3% in favor of donor-arm subjects. Leukemia-free survival was also higher in the donor group: 35.8% vs. 20.6% for the no-donor group.

Improvement in OS for patients receiving transplants was seen across all patient subtypes, regardless of age, response to hypomethylating therapy, and IPSS score. “Treatment effects were seen in any subgroup, but particularly in subjects above age 65,” Dr. Cutler stressed.

In an as-treated analysis that excluded subjects who died, the treatment effects were even more pronounced, with an absolute improvement in OS of 31.4% (47.4% vs. 16% for the no-donor arm) and improvement in leukemia-free survival of 28.4% (39.3% vs. 10.9% for the no-donor arm).

In 25 patients in the no-donor arm who subsequently went on to receive alternate donor transplant, the 3-year OS and leukemia-free survival was 58.5%, underscoring the potential value of alternate donor transplant, Dr. Cutler noted.

Dr. Nakamura emphasized that the gains in survival benefits were not seen at the expense of quality of life, as preliminary results showed no difference in quality-of-life measures across those who received donor transplants and those who did not.

Dr. Brunner noted that physicians often highlight the toxicities of transplant as a consideration for whether to proceed, and while there are toxicities specific to transplant that should be considered, in this study it is seen that, even early on, survival is improved in those patients who move toward early transplant. “It also underscores the limitations of current nontransplant treatments for MDS – there is much room to improve,” he said.
 

Role for alternate donors

Dr. Cutler noted that the majority of patients in the no-donor group died without transplantation. “We need to establish the role of alternative donor transplantation in this population,” he said. Dr. Nakamura indicated that mismatched donors and haploidentical donors such as family donors and umbilical cord blood may be alternate donor sources; outcomes from published studies show similar results, he said.

However, Dr. Brunner noted that the study looked only at traditional fully matched donors, leaving open some questions about alternative donor options such as haploidentical donors and umbilical cord blood donation.

“Our experience in other areas of transplant would suggest that these donor sources may be as good as traditional fully matched options, when using newer conditioning and prophylaxis regimens,” Dr. Brunner said.

Dr. Cutler added, “With the increased acceptance of alternate transplant modalities, we need to determine the outcomes associated with these in prospective trials.”

“I think a significant consideration here as well is health equity,” Dr. Brunner said. “Donor options vary according to race and ethnicity and we need to be proactive as a community to ensure that all MDS patients have access to a potentially curative option early in their diagnosis.”

Dr. Cutler reports consultancy for Mesoblast, Generon, Medsenic, Jazz, Kadmon, and Incyte. Dr. Nakamura reports relationships with Magenta Therapeutics, Kyowa-Kirin, Alexion, Merck, NapaJen Pharma, Kadmon Corporation, Celgene, and Viracor. Dr. Fung has disclosed no relevant financial relationships. Dr. Brodsky reports receiving funding from and being on the board/advisory committee for Achillion Pharmaceuticals, consults with Alexion Pharmaceuticals, and receives honoraria from UpToDate. Dr. Brunner reports relationships with Biogen, Acceleron Pharma Inc, Celgene/BMS, Forty Seven Inc, Jazz Pharma, Novartis, Takeda, Xcenda, GSK, Janssen, and AstraZeneca.

A version of this article originally appeared on Medscape.com.

New clinical data are set to change the treatment landscape for advanced liver cancer.

The data showed that atezolizumab plus bevacizumab improved survival, when compared with sorafenib, in patients with unresectable hepatocellular carcinoma (HCC).

The advanced liver cancer space has been dominated for a more than a decade by sorafenib (Nexavar, Bayer), which was the first systemic therapy to confer “a meaningful survival benefit in the treatment of advanced hepatocellular carcinoma,” notes Robin K. Kelley, MD, from the University of California, San Francisco.

“Since then, no treatment had surpassed the effect of sorafenib in the first line until the regimen of atezolizumab and bevacizumab” that is now being reported, she notes.

The new data come from the IMbrave150 study, published on May 14 in the New England Journal of Medicine.

“The combination of atezolizumab plus bevacizumab has become the new benchmark for first-line therapy in advanced hepatocellular carcinoma,” Kelley writes in an accompanying editorial.

“These data are momentous, since they identify not only the first therapy to improve survival beyond sorafenib, but also the first successful combination regimen and the first positive randomized, phase 3 trial of immune checkpoint inhibition in this challenging cancer,” she added.

The IMbrave 150 study was sponsored by Roche, manufacturer of both the checkpoint inhibitor atezolizumab (Tecentriq, Genentech/Roche) and the antiangiogenic agent bevacizumab (Avastin, Genentech/Roche); the company has submitted an FDA approval application for use of this combination for inoperable liver cancer.

'Results represent a breakthrough'

“These results represent a breakthrough in the management of advanced HCC,” said Josep M. Llovet, MD, PhD, director of the Mount Sinai Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, and professor of medicine in hepatic oncology at the University of Barcelona, Spain.

The combination has already been acknowledged as a milestone in the management of HCC, he said.

Llovet was approached for comment by Medscape Medical News. He was not involved with IMbrave150 but was the lead author on the SHARP study, which led to the first-line approval of sorafenib.

He explained that, since the approval of sorafenib in 2008, lenvatinib (Lenvima, Eisai) has been the only other agent approved for the front-line treatment of HCC after hitting the noninferiority endpoint for survival in comparison with sorafenib. “Up to now, there was no agent superior to sorafenib, the standard of care,” he said.

Now, the combination of atezolizumab-bevacizumab has shown superior efficacy compared with sorafenib, Llovet noted. It is not only the first combination to show efficacy but is also the first checkpoint inhibitor that has demonstrated efficacy in HCC. “Previous studies of checkpoint inhibitors used as single agents in the front-line or second-line setting of advanced liver cancer were negative,” he said.

'Game-changer' in liver cancer

“The atezolizumab-bevacizumab combination is a game-changer in liver cancer,” the lead author of the IMbrave 150 trial, Richard S. Finn, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, told Medscape Medical News.

“The combination has established a new standard of care that is predicated on the gold standard of overall survival [OS] and is underscored by prolonged progression-free survival [PFS] and high response rates that are durable,” Finn said.

In the IMbrave150 trial, treatment-naive patients who had unresectable liver cancer received either atezolizumab-bevacizumab (n = 336) or sorafenib (n = 165).

After a median follow-up of 8.6 months, median survival was significantly longer for the patients who received atezolizumab-bevacizumab: 13.2 months. For the patients who did not receive the combination, median survival was not reached (hazard ratio [HR], 0.58; P < .001). Six-month OS was 84.8% with the combination versus 72.2% with sorafenib.

Median PFS was also significantly longer for patients who received combination therapy: 6.8 months with the combination versus 4.3 months with sorafenib (HR, 0.59; P < .001). Six-month PFS was 54.4% with the combination versus 37.3% with sorafenib.

The objective response rate was 27.3% (complete response, 5.5%) with the combination versus 11.9% (complete response, 0%) with sorafenib

Median time to deterioration of quality of life was also longer for patients who received combination therapy: 11.2 months with atezolizumab-bevacizumab and 3.6 months for sorafenib.

Incidence of grade 3 or 4 adverse events was similar in both arms of the study: 56.5% for the combination versus 55.1% with sorafenib. Adverse events leading to withdrawal from any study drug was not significantly different: 15.5% versus 10.3% for sorafenib.

The percentage of patients who experienced bleeding of any grade (attributed to bevacizumab) was 25.2% with the combination versus 17.3% with sorafenib. In addition, six incidents of fatal bleeding or perforated ulcer were recorded in the combination group, compared with one for the sorafenib group.

Appropriate for all patients?

Llovet told Medscape Medical News that the combination of atezolizumab and bevacizumab, although still awaiting approval for use in liver cancer, will be adopted by guidelines in the management of HCC as first-line therapy.

It has been accepted as the new front-line standard of care in a soon-to-be-published consensus on trial design and endpoints in HCC that he has authored.

Llovet said that the intravenous (IV) dosing of the combination was not likely to be a problem (sorafenib is administered orally). For patients with untreated advanced HCC, median survival is 8 months; it is 11-13 months with sorafenib. With this combination, the median was not reached, but it is expected to be beyond 17 months. “In this scenario, IV versus oral dosing will only have implications if the treatments had similar efficacy but not significantly better performance,” he said.

In her editorial, Kelley suggests caution when considering use of the combination in a patient population broader than that defined by the IMbrave150 study.

She points out that patients in IMbrave150 were required to have well-compensated liver disease (Child-Pugh class A liver function), and patients with untreated or incompletely treated esophageal or gastric varices with bleeding or those who were at high risk of bleeding were excluded from the study.

“Safety has not been established for persons in the Childs-Pugh class B population, and alternative therapies should be considered for patients at high risk for bleeding,” Kelley writes in her editorial.

Bleeding events, including fatal bleeding and perforated ulcers, “underscore important considerations for the application of the atezolizumab-bevacizumab regimen to a broader population beyond the clinical trial setting,” Kelley noted.

She recommends that all patients at risk for varices undergo “appropriate endoscopic evaluation and management before treatment is initiated.”

Llovet agreed and noted that upper endoscopy is not currently practiced in the management of advanced HCC. “One important issue in the clinical practice will be that all patients require an upper endoscopy to rule out esophageal varices, which are at risk of bleeding with bevacizumab,” he said.

Trial investigator Finn explained that IMbrave 150 is not unique and that every phase 3 study has included patients with Child-Pugh class A liver function.

“Patients with Child-Pugh class B are a heterogeneous group of patients,” Finn said. Physicians should use their judgment in providing this combination to patients with Child-Pugh scores of 7–9, he added. “All patients with advanced liver cancer need an endoscopy,” Finn said.

Kelley and Llovet also observed that several ongoing trials, some of which have been completed, are evaluating combinations of immunotherapy and other antiangiogenic agents or combinations of immunotherapies. The results from these trials will inform how such combinations will be used in the future.

Kelley predicted that, if some of these trials are positive, in the absence of a predictive biomarker, physicians will be guided by “the safety profiles of the combinations as well as the inference of synergy on the basis of depth and durability of responses.”

“Results of these trials will be known within the next 12-18 months and might further improve the current standards for patients with inoperable HCC,” Llovet said.

IMbrave150 was sponsored by F. Hoffmann–La Roche/Genentech. Finn has consulted for AtraZeneca, Bayer, Bristol-Myers Squibb, CStone, Eisai, Eli Lilly, Exelixis, Roche, Genentech, Merck & Co, Novartis, and Pfizer. Finn’s coauthors also report relationships with pharmaceutical companies. Kelley reports institutional research support from many pharmaceutical companies and served on the independent data monitoring committee for the IMbrave150 trial. Llovet has received research support from Bayer HealthCare Pharmaceuticals, Eisai, Bristol-Myers Squibb, Boehringer Ingelheim, and Ipsen and consulting fees from Bayer HealthCare Pharmaceuticals, Merck, Eisai Inc, Bristol-Myers Squibb, Celsion Corporation, Eli Lilly, Roche, Genentech, Glycotest, Nucleix, Can-Fite Biopharma, AstraZeneca, and Exelixis.

This article first appeared on Medscape.com.

New clinical data are set to change the treatment landscape for advanced liver cancer.

The data showed that atezolizumab plus bevacizumab improved survival, when compared with sorafenib, in patients with unresectable hepatocellular carcinoma (HCC).

The advanced liver cancer space has been dominated for a more than a decade by sorafenib (Nexavar, Bayer), which was the first systemic therapy to confer “a meaningful survival benefit in the treatment of advanced hepatocellular carcinoma,” notes Robin K. Kelley, MD, from the University of California, San Francisco.

“Since then, no treatment had surpassed the effect of sorafenib in the first line until the regimen of atezolizumab and bevacizumab” that is now being reported, she notes.

The new data come from the IMbrave150 study, published on May 14 in the New England Journal of Medicine.

“The combination of atezolizumab plus bevacizumab has become the new benchmark for first-line therapy in advanced hepatocellular carcinoma,” Kelley writes in an accompanying editorial.

“These data are momentous, since they identify not only the first therapy to improve survival beyond sorafenib, but also the first successful combination regimen and the first positive randomized, phase 3 trial of immune checkpoint inhibition in this challenging cancer,” she added.

The IMbrave 150 study was sponsored by Roche, manufacturer of both the checkpoint inhibitor atezolizumab (Tecentriq, Genentech/Roche) and the antiangiogenic agent bevacizumab (Avastin, Genentech/Roche); the company has submitted an FDA approval application for use of this combination for inoperable liver cancer.

'Results represent a breakthrough'

“These results represent a breakthrough in the management of advanced HCC,” said Josep M. Llovet, MD, PhD, director of the Mount Sinai Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, and professor of medicine in hepatic oncology at the University of Barcelona, Spain.

The combination has already been acknowledged as a milestone in the management of HCC, he said.

Llovet was approached for comment by Medscape Medical News. He was not involved with IMbrave150 but was the lead author on the SHARP study, which led to the first-line approval of sorafenib.

He explained that, since the approval of sorafenib in 2008, lenvatinib (Lenvima, Eisai) has been the only other agent approved for the front-line treatment of HCC after hitting the noninferiority endpoint for survival in comparison with sorafenib. “Up to now, there was no agent superior to sorafenib, the standard of care,” he said.

Now, the combination of atezolizumab-bevacizumab has shown superior efficacy compared with sorafenib, Llovet noted. It is not only the first combination to show efficacy but is also the first checkpoint inhibitor that has demonstrated efficacy in HCC. “Previous studies of checkpoint inhibitors used as single agents in the front-line or second-line setting of advanced liver cancer were negative,” he said.

'Game-changer' in liver cancer

“The atezolizumab-bevacizumab combination is a game-changer in liver cancer,” the lead author of the IMbrave 150 trial, Richard S. Finn, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, told Medscape Medical News.

“The combination has established a new standard of care that is predicated on the gold standard of overall survival [OS] and is underscored by prolonged progression-free survival [PFS] and high response rates that are durable,” Finn said.

In the IMbrave150 trial, treatment-naive patients who had unresectable liver cancer received either atezolizumab-bevacizumab (n = 336) or sorafenib (n = 165).

After a median follow-up of 8.6 months, median survival was significantly longer for the patients who received atezolizumab-bevacizumab: 13.2 months. For the patients who did not receive the combination, median survival was not reached (hazard ratio [HR], 0.58; P < .001). Six-month OS was 84.8% with the combination versus 72.2% with sorafenib.

Median PFS was also significantly longer for patients who received combination therapy: 6.8 months with the combination versus 4.3 months with sorafenib (HR, 0.59; P < .001). Six-month PFS was 54.4% with the combination versus 37.3% with sorafenib.

The objective response rate was 27.3% (complete response, 5.5%) with the combination versus 11.9% (complete response, 0%) with sorafenib

Median time to deterioration of quality of life was also longer for patients who received combination therapy: 11.2 months with atezolizumab-bevacizumab and 3.6 months for sorafenib.

Incidence of grade 3 or 4 adverse events was similar in both arms of the study: 56.5% for the combination versus 55.1% with sorafenib. Adverse events leading to withdrawal from any study drug was not significantly different: 15.5% versus 10.3% for sorafenib.

The percentage of patients who experienced bleeding of any grade (attributed to bevacizumab) was 25.2% with the combination versus 17.3% with sorafenib. In addition, six incidents of fatal bleeding or perforated ulcer were recorded in the combination group, compared with one for the sorafenib group.

Appropriate for all patients?

Llovet told Medscape Medical News that the combination of atezolizumab and bevacizumab, although still awaiting approval for use in liver cancer, will be adopted by guidelines in the management of HCC as first-line therapy.

It has been accepted as the new front-line standard of care in a soon-to-be-published consensus on trial design and endpoints in HCC that he has authored.

Llovet said that the intravenous (IV) dosing of the combination was not likely to be a problem (sorafenib is administered orally). For patients with untreated advanced HCC, median survival is 8 months; it is 11-13 months with sorafenib. With this combination, the median was not reached, but it is expected to be beyond 17 months. “In this scenario, IV versus oral dosing will only have implications if the treatments had similar efficacy but not significantly better performance,” he said.

In her editorial, Kelley suggests caution when considering use of the combination in a patient population broader than that defined by the IMbrave150 study.

She points out that patients in IMbrave150 were required to have well-compensated liver disease (Child-Pugh class A liver function), and patients with untreated or incompletely treated esophageal or gastric varices with bleeding or those who were at high risk of bleeding were excluded from the study.

“Safety has not been established for persons in the Childs-Pugh class B population, and alternative therapies should be considered for patients at high risk for bleeding,” Kelley writes in her editorial.

Bleeding events, including fatal bleeding and perforated ulcers, “underscore important considerations for the application of the atezolizumab-bevacizumab regimen to a broader population beyond the clinical trial setting,” Kelley noted.

She recommends that all patients at risk for varices undergo “appropriate endoscopic evaluation and management before treatment is initiated.”

Llovet agreed and noted that upper endoscopy is not currently practiced in the management of advanced HCC. “One important issue in the clinical practice will be that all patients require an upper endoscopy to rule out esophageal varices, which are at risk of bleeding with bevacizumab,” he said.

Trial investigator Finn explained that IMbrave 150 is not unique and that every phase 3 study has included patients with Child-Pugh class A liver function.

“Patients with Child-Pugh class B are a heterogeneous group of patients,” Finn said. Physicians should use their judgment in providing this combination to patients with Child-Pugh scores of 7–9, he added. “All patients with advanced liver cancer need an endoscopy,” Finn said.

Kelley and Llovet also observed that several ongoing trials, some of which have been completed, are evaluating combinations of immunotherapy and other antiangiogenic agents or combinations of immunotherapies. The results from these trials will inform how such combinations will be used in the future.

Kelley predicted that, if some of these trials are positive, in the absence of a predictive biomarker, physicians will be guided by “the safety profiles of the combinations as well as the inference of synergy on the basis of depth and durability of responses.”

“Results of these trials will be known within the next 12-18 months and might further improve the current standards for patients with inoperable HCC,” Llovet said.

IMbrave150 was sponsored by F. Hoffmann–La Roche/Genentech. Finn has consulted for AtraZeneca, Bayer, Bristol-Myers Squibb, CStone, Eisai, Eli Lilly, Exelixis, Roche, Genentech, Merck & Co, Novartis, and Pfizer. Finn’s coauthors also report relationships with pharmaceutical companies. Kelley reports institutional research support from many pharmaceutical companies and served on the independent data monitoring committee for the IMbrave150 trial. Llovet has received research support from Bayer HealthCare Pharmaceuticals, Eisai, Bristol-Myers Squibb, Boehringer Ingelheim, and Ipsen and consulting fees from Bayer HealthCare Pharmaceuticals, Merck, Eisai Inc, Bristol-Myers Squibb, Celsion Corporation, Eli Lilly, Roche, Genentech, Glycotest, Nucleix, Can-Fite Biopharma, AstraZeneca, and Exelixis.

This article first appeared on Medscape.com.

New clinical data are set to change the treatment landscape for advanced liver cancer.

The data showed that atezolizumab plus bevacizumab improved survival, when compared with sorafenib, in patients with unresectable hepatocellular carcinoma (HCC).

The advanced liver cancer space has been dominated for a more than a decade by sorafenib (Nexavar, Bayer), which was the first systemic therapy to confer “a meaningful survival benefit in the treatment of advanced hepatocellular carcinoma,” notes Robin K. Kelley, MD, from the University of California, San Francisco.

“Since then, no treatment had surpassed the effect of sorafenib in the first line until the regimen of atezolizumab and bevacizumab” that is now being reported, she notes.

The new data come from the IMbrave150 study, published on May 14 in the New England Journal of Medicine.

“The combination of atezolizumab plus bevacizumab has become the new benchmark for first-line therapy in advanced hepatocellular carcinoma,” Kelley writes in an accompanying editorial.

“These data are momentous, since they identify not only the first therapy to improve survival beyond sorafenib, but also the first successful combination regimen and the first positive randomized, phase 3 trial of immune checkpoint inhibition in this challenging cancer,” she added.

The IMbrave 150 study was sponsored by Roche, manufacturer of both the checkpoint inhibitor atezolizumab (Tecentriq, Genentech/Roche) and the antiangiogenic agent bevacizumab (Avastin, Genentech/Roche); the company has submitted an FDA approval application for use of this combination for inoperable liver cancer.

'Results represent a breakthrough'

“These results represent a breakthrough in the management of advanced HCC,” said Josep M. Llovet, MD, PhD, director of the Mount Sinai Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, and professor of medicine in hepatic oncology at the University of Barcelona, Spain.

The combination has already been acknowledged as a milestone in the management of HCC, he said.

Llovet was approached for comment by Medscape Medical News. He was not involved with IMbrave150 but was the lead author on the SHARP study, which led to the first-line approval of sorafenib.

He explained that, since the approval of sorafenib in 2008, lenvatinib (Lenvima, Eisai) has been the only other agent approved for the front-line treatment of HCC after hitting the noninferiority endpoint for survival in comparison with sorafenib. “Up to now, there was no agent superior to sorafenib, the standard of care,” he said.

Now, the combination of atezolizumab-bevacizumab has shown superior efficacy compared with sorafenib, Llovet noted. It is not only the first combination to show efficacy but is also the first checkpoint inhibitor that has demonstrated efficacy in HCC. “Previous studies of checkpoint inhibitors used as single agents in the front-line or second-line setting of advanced liver cancer were negative,” he said.

'Game-changer' in liver cancer

“The atezolizumab-bevacizumab combination is a game-changer in liver cancer,” the lead author of the IMbrave 150 trial, Richard S. Finn, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, told Medscape Medical News.

“The combination has established a new standard of care that is predicated on the gold standard of overall survival [OS] and is underscored by prolonged progression-free survival [PFS] and high response rates that are durable,” Finn said.

In the IMbrave150 trial, treatment-naive patients who had unresectable liver cancer received either atezolizumab-bevacizumab (n = 336) or sorafenib (n = 165).

After a median follow-up of 8.6 months, median survival was significantly longer for the patients who received atezolizumab-bevacizumab: 13.2 months. For the patients who did not receive the combination, median survival was not reached (hazard ratio [HR], 0.58; P < .001). Six-month OS was 84.8% with the combination versus 72.2% with sorafenib.

Median PFS was also significantly longer for patients who received combination therapy: 6.8 months with the combination versus 4.3 months with sorafenib (HR, 0.59; P < .001). Six-month PFS was 54.4% with the combination versus 37.3% with sorafenib.

The objective response rate was 27.3% (complete response, 5.5%) with the combination versus 11.9% (complete response, 0%) with sorafenib

Median time to deterioration of quality of life was also longer for patients who received combination therapy: 11.2 months with atezolizumab-bevacizumab and 3.6 months for sorafenib.

Incidence of grade 3 or 4 adverse events was similar in both arms of the study: 56.5% for the combination versus 55.1% with sorafenib. Adverse events leading to withdrawal from any study drug was not significantly different: 15.5% versus 10.3% for sorafenib.

The percentage of patients who experienced bleeding of any grade (attributed to bevacizumab) was 25.2% with the combination versus 17.3% with sorafenib. In addition, six incidents of fatal bleeding or perforated ulcer were recorded in the combination group, compared with one for the sorafenib group.

Appropriate for all patients?

Llovet told Medscape Medical News that the combination of atezolizumab and bevacizumab, although still awaiting approval for use in liver cancer, will be adopted by guidelines in the management of HCC as first-line therapy.

It has been accepted as the new front-line standard of care in a soon-to-be-published consensus on trial design and endpoints in HCC that he has authored.

Llovet said that the intravenous (IV) dosing of the combination was not likely to be a problem (sorafenib is administered orally). For patients with untreated advanced HCC, median survival is 8 months; it is 11-13 months with sorafenib. With this combination, the median was not reached, but it is expected to be beyond 17 months. “In this scenario, IV versus oral dosing will only have implications if the treatments had similar efficacy but not significantly better performance,” he said.

In her editorial, Kelley suggests caution when considering use of the combination in a patient population broader than that defined by the IMbrave150 study.

She points out that patients in IMbrave150 were required to have well-compensated liver disease (Child-Pugh class A liver function), and patients with untreated or incompletely treated esophageal or gastric varices with bleeding or those who were at high risk of bleeding were excluded from the study.

“Safety has not been established for persons in the Childs-Pugh class B population, and alternative therapies should be considered for patients at high risk for bleeding,” Kelley writes in her editorial.

Bleeding events, including fatal bleeding and perforated ulcers, “underscore important considerations for the application of the atezolizumab-bevacizumab regimen to a broader population beyond the clinical trial setting,” Kelley noted.

She recommends that all patients at risk for varices undergo “appropriate endoscopic evaluation and management before treatment is initiated.”

Llovet agreed and noted that upper endoscopy is not currently practiced in the management of advanced HCC. “One important issue in the clinical practice will be that all patients require an upper endoscopy to rule out esophageal varices, which are at risk of bleeding with bevacizumab,” he said.

Trial investigator Finn explained that IMbrave 150 is not unique and that every phase 3 study has included patients with Child-Pugh class A liver function.

“Patients with Child-Pugh class B are a heterogeneous group of patients,” Finn said. Physicians should use their judgment in providing this combination to patients with Child-Pugh scores of 7–9, he added. “All patients with advanced liver cancer need an endoscopy,” Finn said.

Kelley and Llovet also observed that several ongoing trials, some of which have been completed, are evaluating combinations of immunotherapy and other antiangiogenic agents or combinations of immunotherapies. The results from these trials will inform how such combinations will be used in the future.

Kelley predicted that, if some of these trials are positive, in the absence of a predictive biomarker, physicians will be guided by “the safety profiles of the combinations as well as the inference of synergy on the basis of depth and durability of responses.”

“Results of these trials will be known within the next 12-18 months and might further improve the current standards for patients with inoperable HCC,” Llovet said.

IMbrave150 was sponsored by F. Hoffmann–La Roche/Genentech. Finn has consulted for AtraZeneca, Bayer, Bristol-Myers Squibb, CStone, Eisai, Eli Lilly, Exelixis, Roche, Genentech, Merck & Co, Novartis, and Pfizer. Finn’s coauthors also report relationships with pharmaceutical companies. Kelley reports institutional research support from many pharmaceutical companies and served on the independent data monitoring committee for the IMbrave150 trial. Llovet has received research support from Bayer HealthCare Pharmaceuticals, Eisai, Bristol-Myers Squibb, Boehringer Ingelheim, and Ipsen and consulting fees from Bayer HealthCare Pharmaceuticals, Merck, Eisai Inc, Bristol-Myers Squibb, Celsion Corporation, Eli Lilly, Roche, Genentech, Glycotest, Nucleix, Can-Fite Biopharma, AstraZeneca, and Exelixis.

This article first appeared on Medscape.com.

ORLANDO – For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival – a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).

“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne.

“It’s not too hard to get these patients into remission,” commented another expert. “The problem comes in keeping them in remission.”

Dr. Wei noted that standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60%-80% of patients aged 60 years or younger and in 40%-60% of patients aged 60 years or older.

However, the majority of patients who attain complete remission (CR) will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.

Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Dr. Wei said.

The new results suggest that oral azacitidine could be an effective maintenance therapy.

Dr. Wei presented the results at the 2019 annual meeting of the American Society of Hematology. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.

The results show that CC-486 significantly improved outcomes, compared with placebo plus best supportive care, in terms of median overall survival (24.7 vs. 14.8 months) and median relapse-free survival (10.2 vs. 4.8 months).

The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.
 

Experts predict new standard of care

Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.

“Unlike therapy for acute lymphoblastic leukemia, maintenance therapy has not been part of the treatment algorithm for AML patients in first remission,” Harry P. Erba, MD, PhD, director of the leukemia program at the Duke Cancer Institute, Durham, N.C., told Medscape Medical News.

He explained that trials for maintenance after first remission in AML have failed. Recently, Dr. Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival, compared with observation for older AML patients achieving remission after induction therapy. “However, there was no improvement in overall survival,” he said.

“Remission in AML is short lived,” Dr. Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Dr. Erba said. “Maintenance oral azacitidine will be practice changing,” he predicted.

HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.

“In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy,” Dr. Wei said. He explained that, with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.

Dr. Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). “Long-term maintenance therapy with azacitidine is possible,” he said.

Another expert was also impressed by the new results. “This is an important clinical trial that addresses an unmet need in AML care,” said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the myeloproliferative disorders program at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York.

“Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited,” he explained.

“This large, randomized, double-blind, controlled study of intermediate- or poor-risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant,” Dr. Mascarenhas said.

“This is still not a curative approach,” Dr. Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.
 

Study details

The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status less than or equal to 3 and who had achieved CR or CR with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.

Patients had predominantly de novo AML (89%). Other baseline characteristics of note:

• 85% of patients had intermediate-risk and 15% had poor-risk cytogenetics
• 79% achieved CR and 21% achieved CRi after induction therapy
• 78% received at least one cycle of consolidation therapy
• 43% of patients had minimal residual disease (MRD)–positive disease

Patients were randomized to receive oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.

At a median follow-up of over 41.2 months (3 years, 5 months), median overall survival was significantly longer for patients receiving oral azacitidine at 24.7 months versus 14.8 months for placebo (P less than .0009; hazard ratio, 0.69).

Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine versus 4.8 months for placebo (HR, 0.65; P less than .0001).

Patients on oral azacitidine reported more grade 1-2 gastrointestinal adverse events, such as nausea (65% vs. 24% on placebo), vomiting (60% vs. 10%), and diarrhea (50% vs 22%), as well as more cytopenia. The most common grade 3-4 adverse events were neutropenia (41% with oral azacitidine vs. 24% on placebo), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%).

Although Dr. Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. “The toxicities of continuing on a drug indefinitely are real issues,” he said, explaining that most elderly patients cannot cope with even grade 1-2 nausea, diarrhea, and vomiting over the long term.

But he noted that, regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality of life of patients on oral azacitidine was similar to those on placebo.
 

Awaiting longer follow-up

Both experts said that longer-term follow-up is needed.

“We need a longer follow-up to see how the curves plateau,” Dr. Erba said. He would also like to see a comparative analysis of the data in patients who are MRD negative versus those who are MRD positive.

“The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications,” said Dr. Mascarenhas.

At the press conference, Dr. Wei pointed out that, based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the frontline setting of AML. “The elderly make up about two-thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic,” he said. “Oral azacitidine in the future may also be the backbone for other combinations.”

The study was funded by Celgene.

Dr. Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the board of directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Dr. Wei receives a fraction of its royalty stream related to venetoclax.

A partial list of Dr. Erba’s conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; being on the speakers bureau or receiving lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; being on the data and safety monitoring board of GlycoMimetics; and chairing independent review boards for several trials across several companies.
 

A version of this story originally appeared on Medscape.com.

ORLANDO – For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival – a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).

“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne.

“It’s not too hard to get these patients into remission,” commented another expert. “The problem comes in keeping them in remission.”

Dr. Wei noted that standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60%-80% of patients aged 60 years or younger and in 40%-60% of patients aged 60 years or older.

However, the majority of patients who attain complete remission (CR) will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.

Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Dr. Wei said.

The new results suggest that oral azacitidine could be an effective maintenance therapy.

Dr. Wei presented the results at the 2019 annual meeting of the American Society of Hematology. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.

The results show that CC-486 significantly improved outcomes, compared with placebo plus best supportive care, in terms of median overall survival (24.7 vs. 14.8 months) and median relapse-free survival (10.2 vs. 4.8 months).

The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.
 

Experts predict new standard of care

Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.

“Unlike therapy for acute lymphoblastic leukemia, maintenance therapy has not been part of the treatment algorithm for AML patients in first remission,” Harry P. Erba, MD, PhD, director of the leukemia program at the Duke Cancer Institute, Durham, N.C., told Medscape Medical News.

He explained that trials for maintenance after first remission in AML have failed. Recently, Dr. Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival, compared with observation for older AML patients achieving remission after induction therapy. “However, there was no improvement in overall survival,” he said.

“Remission in AML is short lived,” Dr. Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Dr. Erba said. “Maintenance oral azacitidine will be practice changing,” he predicted.

HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.

“In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy,” Dr. Wei said. He explained that, with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.

Dr. Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). “Long-term maintenance therapy with azacitidine is possible,” he said.

Another expert was also impressed by the new results. “This is an important clinical trial that addresses an unmet need in AML care,” said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the myeloproliferative disorders program at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York.

“Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited,” he explained.

“This large, randomized, double-blind, controlled study of intermediate- or poor-risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant,” Dr. Mascarenhas said.

“This is still not a curative approach,” Dr. Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.
 

Study details

The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status less than or equal to 3 and who had achieved CR or CR with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.

Patients had predominantly de novo AML (89%). Other baseline characteristics of note:

• 85% of patients had intermediate-risk and 15% had poor-risk cytogenetics
• 79% achieved CR and 21% achieved CRi after induction therapy
• 78% received at least one cycle of consolidation therapy
• 43% of patients had minimal residual disease (MRD)–positive disease

Patients were randomized to receive oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.

At a median follow-up of over 41.2 months (3 years, 5 months), median overall survival was significantly longer for patients receiving oral azacitidine at 24.7 months versus 14.8 months for placebo (P less than .0009; hazard ratio, 0.69).

Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine versus 4.8 months for placebo (HR, 0.65; P less than .0001).

Patients on oral azacitidine reported more grade 1-2 gastrointestinal adverse events, such as nausea (65% vs. 24% on placebo), vomiting (60% vs. 10%), and diarrhea (50% vs 22%), as well as more cytopenia. The most common grade 3-4 adverse events were neutropenia (41% with oral azacitidine vs. 24% on placebo), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%).

Although Dr. Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. “The toxicities of continuing on a drug indefinitely are real issues,” he said, explaining that most elderly patients cannot cope with even grade 1-2 nausea, diarrhea, and vomiting over the long term.

But he noted that, regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality of life of patients on oral azacitidine was similar to those on placebo.
 

Awaiting longer follow-up

Both experts said that longer-term follow-up is needed.

“We need a longer follow-up to see how the curves plateau,” Dr. Erba said. He would also like to see a comparative analysis of the data in patients who are MRD negative versus those who are MRD positive.

“The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications,” said Dr. Mascarenhas.

At the press conference, Dr. Wei pointed out that, based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the frontline setting of AML. “The elderly make up about two-thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic,” he said. “Oral azacitidine in the future may also be the backbone for other combinations.”

The study was funded by Celgene.

Dr. Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the board of directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Dr. Wei receives a fraction of its royalty stream related to venetoclax.

A partial list of Dr. Erba’s conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; being on the speakers bureau or receiving lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; being on the data and safety monitoring board of GlycoMimetics; and chairing independent review boards for several trials across several companies.
 

A version of this story originally appeared on Medscape.com.

ORLANDO – For the first time, there is a maintenance therapy for patients with acute myeloid leukemia (AML) in remission that can improve overall survival – a new oral formulation of an old drug, azacitidine, known as CC-486 (Celgene).

“Oral azacitidine represents a new therapeutic standard for patients with AML in remission,” said lead author Andrew H. Wei, MBBS, PhD, from the Alfred Hospital in Melbourne.

“It’s not too hard to get these patients into remission,” commented another expert. “The problem comes in keeping them in remission.”

Dr. Wei noted that standard treatment with intensive induction chemotherapy for AML induces complete remission (CR) in 60%-80% of patients aged 60 years or younger and in 40%-60% of patients aged 60 years or older.

However, the majority of patients who attain complete remission (CR) will eventually relapse, and relapse is the primary obstacle to long-term survival, he said.

Despite various attempts, there has been no success over the past 30 years in defining maintenance treatment for these patients, Dr. Wei said.

The new results suggest that oral azacitidine could be an effective maintenance therapy.

Dr. Wei presented the results at the 2019 annual meeting of the American Society of Hematology. They come from the QUAZAR AML-001 study, conducted in 472 patients with poor-risk AML in first remission.

The results show that CC-486 significantly improved outcomes, compared with placebo plus best supportive care, in terms of median overall survival (24.7 vs. 14.8 months) and median relapse-free survival (10.2 vs. 4.8 months).

The trial was funded by Celgene, which said it will be submitting the data for regulatory approval for the new oral formulation of azacitidine, CC-486.
 

Experts predict new standard of care

Experts approached for comment agreed that maintenance oral azacitidine will become the new standard of care for patients with AML in first remission.

“Unlike therapy for acute lymphoblastic leukemia, maintenance therapy has not been part of the treatment algorithm for AML patients in first remission,” Harry P. Erba, MD, PhD, director of the leukemia program at the Duke Cancer Institute, Durham, N.C., told Medscape Medical News.

He explained that trials for maintenance after first remission in AML have failed. Recently, Dr. Erba noted, the HOVON97 trial with injectable azacitidine demonstrated improvement in relapse-free survival, compared with observation for older AML patients achieving remission after induction therapy. “However, there was no improvement in overall survival,” he said.

“Remission in AML is short lived,” Dr. Erba said. Oral azacitidine represents the first maintenance therapy in AML that has shown both significant and clinically meaningful improvements in overall and relapse-free survival and will represent a new standard of care for patients with AML in remission, Dr. Erba said. “Maintenance oral azacitidine will be practice changing,” he predicted.

HOVON97 was a small study of injectable azacitidine used as maintenance therapy for 12 months, but it was slow to accrue and did not meet its accrual target.

“In HOVON97, at 12 months, only one third of patients received less than the 12 cycles of therapy,” Dr. Wei said. He explained that, with injectable azacitidine, patients have to come into the hospital/clinic for 7 days a month, 84 days a year. Oral azacitidine is more convenient as patients do not have to come into the clinic, he said.

Dr. Wei pointed out that about 40 patients in the QUAZAR study, which started in 2013, are still on maintenance therapy, with one patient now having received 80 cycles of therapy (approximately 7 years). “Long-term maintenance therapy with azacitidine is possible,” he said.

Another expert was also impressed by the new results. “This is an important clinical trial that addresses an unmet need in AML care,” said John Mascarenhas, MD, director of the Adult Leukemia Program and leader of clinical investigation within the myeloproliferative disorders program at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, New York.

“Older patients can often receive induction chemotherapy but frequently do not ultimately do well, as the disease relapses and survival is limited,” he explained.

“This large, randomized, double-blind, controlled study of intermediate- or poor-risk AML patients over the age of 55 years supports the use of maintenance oral azacitidine after initial remission to extend overall and relapse-free survival in older AML patients not eligible for transplant,” Dr. Mascarenhas said.

“This is still not a curative approach,” Dr. Wei said, but added that it prolongs relapse-free survival for older patients while maintaining a quality of life for as long as possible.
 

Study details

The QUAZAR phase 3 study enrolled patients with poor- or intermediate-risk cytogenetics who had an Eastern Cooperative Oncology Group performance status less than or equal to 3 and who had achieved CR or CR with incomplete count recovery (CRi) after induction therapy with or without consolidation therapy. In addition, patients were not candidates for stem cell transplants.

Patients had predominantly de novo AML (89%). Other baseline characteristics of note:

• 85% of patients had intermediate-risk and 15% had poor-risk cytogenetics
• 79% achieved CR and 21% achieved CRi after induction therapy
• 78% received at least one cycle of consolidation therapy
• 43% of patients had minimal residual disease (MRD)–positive disease

Patients were randomized to receive oral azacitidine 200 mg daily on days 1-14 of a repeat 28-day cycle (n = 278) or matching placebo (n = 274). Treatment was continued indefinitely until blast count was more than 15% or patients experienced unacceptable toxicity or went on to transplant.

At a median follow-up of over 41.2 months (3 years, 5 months), median overall survival was significantly longer for patients receiving oral azacitidine at 24.7 months versus 14.8 months for placebo (P less than .0009; hazard ratio, 0.69).

Relapse-free survival was also significantly prolonged, to 10.2 months for patients on oral azacitidine versus 4.8 months for placebo (HR, 0.65; P less than .0001).

Patients on oral azacitidine reported more grade 1-2 gastrointestinal adverse events, such as nausea (65% vs. 24% on placebo), vomiting (60% vs. 10%), and diarrhea (50% vs 22%), as well as more cytopenia. The most common grade 3-4 adverse events were neutropenia (41% with oral azacitidine vs. 24% on placebo), thrombocytopenia (23% vs. 22%), and anemia (14% vs. 13%).

Although Dr. Erba supported the use of oral azacitidine as maintenance therapy, he pointed out that it was hard to convince patients, especially older ones, to continue on maintenance therapy indefinitely. “The toxicities of continuing on a drug indefinitely are real issues,” he said, explaining that most elderly patients cannot cope with even grade 1-2 nausea, diarrhea, and vomiting over the long term.

But he noted that, regardless of the higher incidence of some adverse events with oral azacitidine, the health-related quality of life of patients on oral azacitidine was similar to those on placebo.
 

Awaiting longer follow-up

Both experts said that longer-term follow-up is needed.

“We need a longer follow-up to see how the curves plateau,” Dr. Erba said. He would also like to see a comparative analysis of the data in patients who are MRD negative versus those who are MRD positive.

“The final results of this study, including the impact of measurable residual disease on outcome in this setting, will potentially have practice-changing implications,” said Dr. Mascarenhas.

At the press conference, Dr. Wei pointed out that, based on the data from QUAZAR, oral azacitidine is likely to be evaluated in the frontline setting of AML. “The elderly make up about two-thirds of all AML patients, and oral azacitidine will be a better option than 7 days per month for chemotherapy treatment in the clinic,” he said. “Oral azacitidine in the future may also be the backbone for other combinations.”

The study was funded by Celgene.

Dr. Wei receives honoraria from AbbVie, Macrogenics, Pfizer, Astellas, Janssen, Servier, Celgene, Amgen, AstraZeneca, Novartis, and Genentech; is on the board of directors or serves on the advisory committees for AbbVie, Macrogenics, Pfizer, Astellas, Servier, Celgene, Amgen, Novartis, and Genentech; and receives research funding from AbbVie, Servier, Celgene, Amgen, AstraZeneca, and Novartis. As a former employee of the Walter and Eliza Hall Institute, Dr. Wei receives a fraction of its royalty stream related to venetoclax.

A partial list of Dr. Erba’s conflict of interest includes consulting with Agios, Novartis, Daiichi Sankyo, MacroGenics, Jazz Pharmaceuticals, Seattle Genetics, GlycoMimetics, Amgen, Pfizer, Celgene, AbbVie, Covance, Immunogen, Astellas Pharma, Incyte; being on the speakers bureau or receiving lecture fees from Agios, Novartis, MacroGenics, Jazz Pharmaceuticals, Celgene; receiving research funding from Novartis, Daiichi Sankyo, MacroGenics, GlycoMimetics, Celgene; being on the data and safety monitoring board of GlycoMimetics; and chairing independent review boards for several trials across several companies.
 

A version of this story originally appeared on Medscape.com.

Photo by Rhoda Baer

Research has shown an increase in the global incidence of leukemia and non-Hodgkin lymphoma (NHL) in recent years.

The Global Burden of Disease (GBD) study showed that, from 2006 to 2016, the incidence of NHL increased 45%, and the incidence of leukemia increased 26%.

These increases were largely due to population growth and aging.

Results from the GDB study were published in JAMA Oncology.

The study indicated that, in 2016, there were 17.2 million cases of cancer worldwide and 8.9 million cancer deaths.

One in 3 men were likely to get cancer during their lifetime, as were 1 in 5 women. Cancer was associated with 213.2 million disability-adjusted life years (DALYs).

The following table lists the 2016 global incidence and mortality figures for all cancers combined and for individual hematologic malignancies.

Leukemia

In 2016, there were 467,000 new cases of leukemia and 310,000 leukemia deaths. Leukemia was responsible for 10.2 million DALYs. Leukemia developed in 1 in 118 men and 1 in 194 women worldwide.

Between 2006 and 2016, the global leukemia incidence increased by 26%—from 370,482 to 466,802 cases.

The researchers said the factors contributing to this increase were population growth (12%), population aging (10%), and an increase in age-specific incidence rates (3%).

NHL

In 2016, there were 461,000 new cases of NHL and 240,000 NHL deaths. NHL was responsible for 6.8 million DALYs. NHL developed in 1 in 110 men and 1 in 161 women worldwide.

Between 2006 and 2016, NHL increased by 45%, from 319,078 to 461,164 cases.

The factors contributing to this increase were increasing age-specific incidence rates (17%), changing population age structure (15%), and population growth (12%).

“A large proportion of the increase in cancer incidence can be explained by improving life expectancy and population growth—a development that can at least partially be attributed to a reduced burden from other common diseases,” the study authors wrote.

The authors also pointed out that prevention efforts are less effective for hematologic malignancies than for other cancers.

Photo by Rhoda Baer

Research has shown an increase in the global incidence of leukemia and non-Hodgkin lymphoma (NHL) in recent years.

The Global Burden of Disease (GBD) study showed that, from 2006 to 2016, the incidence of NHL increased 45%, and the incidence of leukemia increased 26%.

These increases were largely due to population growth and aging.

Results from the GDB study were published in JAMA Oncology.

The study indicated that, in 2016, there were 17.2 million cases of cancer worldwide and 8.9 million cancer deaths.

One in 3 men were likely to get cancer during their lifetime, as were 1 in 5 women. Cancer was associated with 213.2 million disability-adjusted life years (DALYs).

The following table lists the 2016 global incidence and mortality figures for all cancers combined and for individual hematologic malignancies.

Leukemia

In 2016, there were 467,000 new cases of leukemia and 310,000 leukemia deaths. Leukemia was responsible for 10.2 million DALYs. Leukemia developed in 1 in 118 men and 1 in 194 women worldwide.

Between 2006 and 2016, the global leukemia incidence increased by 26%—from 370,482 to 466,802 cases.

The researchers said the factors contributing to this increase were population growth (12%), population aging (10%), and an increase in age-specific incidence rates (3%).

NHL

In 2016, there were 461,000 new cases of NHL and 240,000 NHL deaths. NHL was responsible for 6.8 million DALYs. NHL developed in 1 in 110 men and 1 in 161 women worldwide.

Between 2006 and 2016, NHL increased by 45%, from 319,078 to 461,164 cases.

The factors contributing to this increase were increasing age-specific incidence rates (17%), changing population age structure (15%), and population growth (12%).

“A large proportion of the increase in cancer incidence can be explained by improving life expectancy and population growth—a development that can at least partially be attributed to a reduced burden from other common diseases,” the study authors wrote.

The authors also pointed out that prevention efforts are less effective for hematologic malignancies than for other cancers.

Photo by Rhoda Baer

Research has shown an increase in the global incidence of leukemia and non-Hodgkin lymphoma (NHL) in recent years.

The Global Burden of Disease (GBD) study showed that, from 2006 to 2016, the incidence of NHL increased 45%, and the incidence of leukemia increased 26%.

These increases were largely due to population growth and aging.

Results from the GDB study were published in JAMA Oncology.

The study indicated that, in 2016, there were 17.2 million cases of cancer worldwide and 8.9 million cancer deaths.

One in 3 men were likely to get cancer during their lifetime, as were 1 in 5 women. Cancer was associated with 213.2 million disability-adjusted life years (DALYs).

The following table lists the 2016 global incidence and mortality figures for all cancers combined and for individual hematologic malignancies.

Leukemia

In 2016, there were 467,000 new cases of leukemia and 310,000 leukemia deaths. Leukemia was responsible for 10.2 million DALYs. Leukemia developed in 1 in 118 men and 1 in 194 women worldwide.

Between 2006 and 2016, the global leukemia incidence increased by 26%—from 370,482 to 466,802 cases.

The researchers said the factors contributing to this increase were population growth (12%), population aging (10%), and an increase in age-specific incidence rates (3%).

NHL

In 2016, there were 461,000 new cases of NHL and 240,000 NHL deaths. NHL was responsible for 6.8 million DALYs. NHL developed in 1 in 110 men and 1 in 161 women worldwide.

Between 2006 and 2016, NHL increased by 45%, from 319,078 to 461,164 cases.

The factors contributing to this increase were increasing age-specific incidence rates (17%), changing population age structure (15%), and population growth (12%).

“A large proportion of the increase in cancer incidence can be explained by improving life expectancy and population growth—a development that can at least partially be attributed to a reduced burden from other common diseases,” the study authors wrote.

The authors also pointed out that prevention efforts are less effective for hematologic malignancies than for other cancers.

Hospital of Philadelphia

A kinase called heme-regulated inhibitor (HRI) could be a therapeutic target for sickle cell disease (SCD) and some forms of β-thalassemia, according to researchers.

The team found that reducing the activity of HRI (also known as EIF2AK1) can boost the production of fetal hemoglobin (HbF).

Gerd Blobel MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported this discovery in Science.

Dr Blobel noted that hydroxyurea remains the only approved drug that can increase fetal Hb in adults.

“Our goal was to identify new potential drug targets that regulate fetal Hb levels,” he said.

To that end, the researchers conducted a CRISPR-Cas9 screen targeting protein kinases. They designed a library of single-guide RNAs targeting 482 kinase domains, which covered almost all known kinases in the human genome.

The team attempted to determine if interference with any of the kinases in an immortalized human red blood cell line would increase HbF levels.

Results suggested that HRI, an erythroid-specific kinase that controls protein translation, is a repressor of HbF.

To confirm that HRI plays a key role in regulating HbF levels, the researchers depleted HRI in primary cultured human red blood cell precursors.

Reduced activity of HRI resulted in decreased phosphorylation of eIF2a and increased levels of HbF, but interfering with HRI levels did not impair cell viability or maturation.

The researchers next showed that HRI was a repressor of HbF in cultured primary cells from patients with SCD.

When HRI levels were artificially reduced, HbF levels were significantly increased, and cells were less prone to sickling. This suggested to the researchers that “HRI depletion may achieve therapeutically relevant levels of HbF.”

Mechanistically, the effects of HRI on HbF were shown to occur, in large measure, through modulating the activity of BCL11A, a direct repressor of HbF transcription.

The observation that HRI inhibition elevated HbF levels and reduced cell sickling in culture suggested that future pharmacologic HRI inhibitors might provide clinical benefit in patients with SCD.

To that end, an important aspect of this work was to determine if the effect of HRI inhibition could be increased with another drug added to the mix, Dr Blobel said.

He and his colleagues therefore tested whether pomalidomide, which was previously shown to increase HbF in an experimental setting, could be such a drug.

HRI depletion in combination with pomalidomide treatment raised HbF levels more than either treatment alone, suggesting that HRI inhibition might be combined with another HbF-inducing drug to increase the therapeutic index.

Hospital of Philadelphia

A kinase called heme-regulated inhibitor (HRI) could be a therapeutic target for sickle cell disease (SCD) and some forms of β-thalassemia, according to researchers.

The team found that reducing the activity of HRI (also known as EIF2AK1) can boost the production of fetal hemoglobin (HbF).

Gerd Blobel MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported this discovery in Science.

Dr Blobel noted that hydroxyurea remains the only approved drug that can increase fetal Hb in adults.

“Our goal was to identify new potential drug targets that regulate fetal Hb levels,” he said.

To that end, the researchers conducted a CRISPR-Cas9 screen targeting protein kinases. They designed a library of single-guide RNAs targeting 482 kinase domains, which covered almost all known kinases in the human genome.

The team attempted to determine if interference with any of the kinases in an immortalized human red blood cell line would increase HbF levels.

Results suggested that HRI, an erythroid-specific kinase that controls protein translation, is a repressor of HbF.

To confirm that HRI plays a key role in regulating HbF levels, the researchers depleted HRI in primary cultured human red blood cell precursors.

Reduced activity of HRI resulted in decreased phosphorylation of eIF2a and increased levels of HbF, but interfering with HRI levels did not impair cell viability or maturation.

The researchers next showed that HRI was a repressor of HbF in cultured primary cells from patients with SCD.

When HRI levels were artificially reduced, HbF levels were significantly increased, and cells were less prone to sickling. This suggested to the researchers that “HRI depletion may achieve therapeutically relevant levels of HbF.”

Mechanistically, the effects of HRI on HbF were shown to occur, in large measure, through modulating the activity of BCL11A, a direct repressor of HbF transcription.

The observation that HRI inhibition elevated HbF levels and reduced cell sickling in culture suggested that future pharmacologic HRI inhibitors might provide clinical benefit in patients with SCD.

To that end, an important aspect of this work was to determine if the effect of HRI inhibition could be increased with another drug added to the mix, Dr Blobel said.

He and his colleagues therefore tested whether pomalidomide, which was previously shown to increase HbF in an experimental setting, could be such a drug.

HRI depletion in combination with pomalidomide treatment raised HbF levels more than either treatment alone, suggesting that HRI inhibition might be combined with another HbF-inducing drug to increase the therapeutic index.

Hospital of Philadelphia

A kinase called heme-regulated inhibitor (HRI) could be a therapeutic target for sickle cell disease (SCD) and some forms of β-thalassemia, according to researchers.

The team found that reducing the activity of HRI (also known as EIF2AK1) can boost the production of fetal hemoglobin (HbF).

Gerd Blobel MD, PhD, of The Children’s Hospital of Philadelphia in Pennsylvania, and his colleagues reported this discovery in Science.

Dr Blobel noted that hydroxyurea remains the only approved drug that can increase fetal Hb in adults.

“Our goal was to identify new potential drug targets that regulate fetal Hb levels,” he said.

To that end, the researchers conducted a CRISPR-Cas9 screen targeting protein kinases. They designed a library of single-guide RNAs targeting 482 kinase domains, which covered almost all known kinases in the human genome.

The team attempted to determine if interference with any of the kinases in an immortalized human red blood cell line would increase HbF levels.

Results suggested that HRI, an erythroid-specific kinase that controls protein translation, is a repressor of HbF.

To confirm that HRI plays a key role in regulating HbF levels, the researchers depleted HRI in primary cultured human red blood cell precursors.

Reduced activity of HRI resulted in decreased phosphorylation of eIF2a and increased levels of HbF, but interfering with HRI levels did not impair cell viability or maturation.

The researchers next showed that HRI was a repressor of HbF in cultured primary cells from patients with SCD.

When HRI levels were artificially reduced, HbF levels were significantly increased, and cells were less prone to sickling. This suggested to the researchers that “HRI depletion may achieve therapeutically relevant levels of HbF.”

Mechanistically, the effects of HRI on HbF were shown to occur, in large measure, through modulating the activity of BCL11A, a direct repressor of HbF transcription.

The observation that HRI inhibition elevated HbF levels and reduced cell sickling in culture suggested that future pharmacologic HRI inhibitors might provide clinical benefit in patients with SCD.

To that end, an important aspect of this work was to determine if the effect of HRI inhibition could be increased with another drug added to the mix, Dr Blobel said.

He and his colleagues therefore tested whether pomalidomide, which was previously shown to increase HbF in an experimental setting, could be such a drug.

HRI depletion in combination with pomalidomide treatment raised HbF levels more than either treatment alone, suggesting that HRI inhibition might be combined with another HbF-inducing drug to increase the therapeutic index.

Photo courtesy of the CDC

Clinical trials supporting the approval of drugs with breakthrough therapy designation¹ do not meet the same standards as trials for non-breakthrough drugs, according to researchers.

Between 2012 and 2017, the US Food and Drug Administration (FDA) approved 46 breakthrough therapeutics on the basis of 89 pivotal trials.

Researchers found these trials “commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary endpoints, and enrolled small numbers of patients.”

Joseph S. Ross, MD, of the Yale School of Medicine in New Haven, Connecticut, and his colleagues detailed these findings in a letter to JAMA.

“To be clear, I think the FDA, as directed by Congress, is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions,” Dr Ross said.

“Our research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non-breakthrough therapy drugs.”

Analyzing the approvals

More than half of the 46 approvals analyzed were for cancer therapeutics (n=25; 54.3%), and an equal number were considered first-in-class.

All 46 products received priority review², 30 (65.2%) received orphan designation³, 24 qualified for fast track⁴ review (52.2%), and 18 received accelerated approval⁵ (39.1%).

The median time from an investigational new drug activation to final FDA approval was 4.9 years. The median time from the submission of the new drug application to FDA approval was 6.9 months.

The median number of pivotal trials per indication was 1, and the median number of patients supporting an indication was 222.

Of all the approvals, 27 (58.7%) were made based on randomized trials, 21 (45.7%) were based on double-blind allocation, and 25 (54.3%) used an active or placebo comparator. Only 10 (21.7%) used a clinical primary endpoint.

The analysis also showed that trials supporting breakthrough drugs with accelerated approval were significantly less likely to be randomized, double-blinded, or have an active/placebo control group.

Of 18 trials that were used to grant drugs accelerated approval, 3 (16.7%) trials were randomized, 1 (5.6%) was double-blinded, and 3 (16.7%) had an active/placebo control group.

Of 28 trials supporting drugs without accelerated approval, 24 (85.7%) trials were randomized, 20 (71.4%) were double-blinded, and 22 (78.6%) had an active/placebo control group.

All 18 accelerated approvals had at least 1 safety analysis or efficacy-focused postmarketing requirement.

Dr Ross pointed out that when approvals are based on shorter and smaller clinical trials, there is greater uncertainty at the time of approval.

For example, will effects observed in a small, single trial be observed in a larger population or in another independent study? Will effects observed over a short period persist over time? Will new risks (or benefits) be observed over a longer period? And will the effect observed on the outcomes used in these shorter trials—usually surrogate endpoints believed to predict a clinical benefit—be confirmed by clinical outcomes?

“If we are going to be making this trade-off to allow novel drugs to come to market on the basis of evidence that is generally accompanied by greater uncertainty, we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarketing trials are conducted within a reasonable period of time,” Dr Ross said.

He noted that postmarketing trials will resolve some of the uncertainty and will ensure that drugs are associated with the benefit/safety profile that is expected based on the initial clinical studies.

“This will allow clinicians and patients to make fully informed decisions about whether to use these novel treatments,” he said.

1. The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review. To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

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

3. The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US. Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

4. The FDA’s fast track program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs. Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers. Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.

5. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition. Accelerated approval is based on surrogate or intermediate endpoints that are reasonably likely to predict clinical benefit. Continued approval of drugs granted accelerated approval may be contingent upon verification of clinical benefit in confirmatory trials.

Photo courtesy of the CDC

Clinical trials supporting the approval of drugs with breakthrough therapy designation¹ do not meet the same standards as trials for non-breakthrough drugs, according to researchers.

Between 2012 and 2017, the US Food and Drug Administration (FDA) approved 46 breakthrough therapeutics on the basis of 89 pivotal trials.

Researchers found these trials “commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary endpoints, and enrolled small numbers of patients.”

Joseph S. Ross, MD, of the Yale School of Medicine in New Haven, Connecticut, and his colleagues detailed these findings in a letter to JAMA.

“To be clear, I think the FDA, as directed by Congress, is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions,” Dr Ross said.

“Our research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non-breakthrough therapy drugs.”

Analyzing the approvals

More than half of the 46 approvals analyzed were for cancer therapeutics (n=25; 54.3%), and an equal number were considered first-in-class.

All 46 products received priority review², 30 (65.2%) received orphan designation³, 24 qualified for fast track⁴ review (52.2%), and 18 received accelerated approval⁵ (39.1%).

The median time from an investigational new drug activation to final FDA approval was 4.9 years. The median time from the submission of the new drug application to FDA approval was 6.9 months.

The median number of pivotal trials per indication was 1, and the median number of patients supporting an indication was 222.

Of all the approvals, 27 (58.7%) were made based on randomized trials, 21 (45.7%) were based on double-blind allocation, and 25 (54.3%) used an active or placebo comparator. Only 10 (21.7%) used a clinical primary endpoint.

The analysis also showed that trials supporting breakthrough drugs with accelerated approval were significantly less likely to be randomized, double-blinded, or have an active/placebo control group.

Of 18 trials that were used to grant drugs accelerated approval, 3 (16.7%) trials were randomized, 1 (5.6%) was double-blinded, and 3 (16.7%) had an active/placebo control group.

Of 28 trials supporting drugs without accelerated approval, 24 (85.7%) trials were randomized, 20 (71.4%) were double-blinded, and 22 (78.6%) had an active/placebo control group.

All 18 accelerated approvals had at least 1 safety analysis or efficacy-focused postmarketing requirement.

Dr Ross pointed out that when approvals are based on shorter and smaller clinical trials, there is greater uncertainty at the time of approval.

For example, will effects observed in a small, single trial be observed in a larger population or in another independent study? Will effects observed over a short period persist over time? Will new risks (or benefits) be observed over a longer period? And will the effect observed on the outcomes used in these shorter trials—usually surrogate endpoints believed to predict a clinical benefit—be confirmed by clinical outcomes?

“If we are going to be making this trade-off to allow novel drugs to come to market on the basis of evidence that is generally accompanied by greater uncertainty, we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarketing trials are conducted within a reasonable period of time,” Dr Ross said.

He noted that postmarketing trials will resolve some of the uncertainty and will ensure that drugs are associated with the benefit/safety profile that is expected based on the initial clinical studies.

“This will allow clinicians and patients to make fully informed decisions about whether to use these novel treatments,” he said.

1. The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review. To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

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

3. The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US. Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

4. The FDA’s fast track program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs. Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers. Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.

5. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition. Accelerated approval is based on surrogate or intermediate endpoints that are reasonably likely to predict clinical benefit. Continued approval of drugs granted accelerated approval may be contingent upon verification of clinical benefit in confirmatory trials.

Photo courtesy of the CDC

Clinical trials supporting the approval of drugs with breakthrough therapy designation¹ do not meet the same standards as trials for non-breakthrough drugs, according to researchers.

Between 2012 and 2017, the US Food and Drug Administration (FDA) approved 46 breakthrough therapeutics on the basis of 89 pivotal trials.

Researchers found these trials “commonly lacked randomization, double-blinding, and control groups, used surrogate markers as primary endpoints, and enrolled small numbers of patients.”

Joseph S. Ross, MD, of the Yale School of Medicine in New Haven, Connecticut, and his colleagues detailed these findings in a letter to JAMA.

“To be clear, I think the FDA, as directed by Congress, is doing everything it can to expedite the development and review of drugs that treat serious and life-threatening conditions,” Dr Ross said.

“Our research suggests that FDA approval of these breakthrough therapies is generally based on shorter and smaller clinical trials than those that support FDA approval of non-breakthrough therapy drugs.”

Analyzing the approvals

More than half of the 46 approvals analyzed were for cancer therapeutics (n=25; 54.3%), and an equal number were considered first-in-class.

All 46 products received priority review², 30 (65.2%) received orphan designation³, 24 qualified for fast track⁴ review (52.2%), and 18 received accelerated approval⁵ (39.1%).

The median time from an investigational new drug activation to final FDA approval was 4.9 years. The median time from the submission of the new drug application to FDA approval was 6.9 months.

The median number of pivotal trials per indication was 1, and the median number of patients supporting an indication was 222.

Of all the approvals, 27 (58.7%) were made based on randomized trials, 21 (45.7%) were based on double-blind allocation, and 25 (54.3%) used an active or placebo comparator. Only 10 (21.7%) used a clinical primary endpoint.

The analysis also showed that trials supporting breakthrough drugs with accelerated approval were significantly less likely to be randomized, double-blinded, or have an active/placebo control group.

Of 18 trials that were used to grant drugs accelerated approval, 3 (16.7%) trials were randomized, 1 (5.6%) was double-blinded, and 3 (16.7%) had an active/placebo control group.

Of 28 trials supporting drugs without accelerated approval, 24 (85.7%) trials were randomized, 20 (71.4%) were double-blinded, and 22 (78.6%) had an active/placebo control group.

All 18 accelerated approvals had at least 1 safety analysis or efficacy-focused postmarketing requirement.

Dr Ross pointed out that when approvals are based on shorter and smaller clinical trials, there is greater uncertainty at the time of approval.

For example, will effects observed in a small, single trial be observed in a larger population or in another independent study? Will effects observed over a short period persist over time? Will new risks (or benefits) be observed over a longer period? And will the effect observed on the outcomes used in these shorter trials—usually surrogate endpoints believed to predict a clinical benefit—be confirmed by clinical outcomes?

“If we are going to be making this trade-off to allow novel drugs to come to market on the basis of evidence that is generally accompanied by greater uncertainty, we must be committed as a clinical and scientific community to ensuring that high-quality, rigorous postmarketing trials are conducted within a reasonable period of time,” Dr Ross said.

He noted that postmarketing trials will resolve some of the uncertainty and will ensure that drugs are associated with the benefit/safety profile that is expected based on the initial clinical studies.

“This will allow clinicians and patients to make fully informed decisions about whether to use these novel treatments,” he said.

1. The FDA’s breakthrough designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions. Breakthrough designation entitles sponsors to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as rolling submission and priority review. To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

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

3. The FDA grants orphan designation to products intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US. Orphan designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

4. The FDA’s fast track program is designed to expedite clinical development and submission of applications for drugs with the potential to treat serious or life-threatening conditions and address unmet medical needs. Fast track designation facilitates frequent interactions with the FDA review team, including meetings to discuss the drug’s development plan and written communications about issues such as trial design and use of biomarkers. Drugs that receive fast track designation may be eligible for accelerated approval and priority review if relevant criteria are met. Fast track drugs may also be eligible for rolling review, which allows a developer to submit individual sections of a drug’s application for review as they are ready, rather than waiting until all sections are complete.

5. The FDA’s accelerated approval program allows conditional approval of a drug that fills an unmet medical need for a serious condition. Accelerated approval is based on surrogate or intermediate endpoints that are reasonably likely to predict clinical benefit. Continued approval of drugs granted accelerated approval may be contingent upon verification of clinical benefit in confirmatory trials.

Image from Jens Langner

In the PETAL trial, treatment intensification based on results of an interim positron emission tomography (PET) scan did not improve survival outcomes for patients with aggressive lymphomas.

PET-positive patients did not benefit by switching from R-CHOP to a more intensive chemotherapy regimen.

PET-negative patients did not benefit from 2 additional cycles of rituximab after R-CHOP.

These results were published in the Journal of Clinical Oncology.

PETAL was a randomized trial of patients with newly diagnosed T- or B-cell lymphomas.

Patients received 2 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)—plus rituximab (R-CHOP) in CD20-positive lymphomas—followed by a PET scan.

PET-positive patients were randomized to receive 6 additional cycles of R-CHOP or 6 blocks of an intensive protocol used to treat Burkitt lymphoma. This protocol consisted of high-dose methotrexate, cytarabine, hyperfractionated cyclophosphamide and ifosfamide, split-dose doxorubicin and etoposide, vincristine, vindesine, and dexamethasone.

PET-negative patients with CD20-positive lymphomas were randomized to receive 4 additional cycles of R-CHOP or 4 additional cycles of R-CHOP followed by 2 more doses of rituximab.

Among patients with T-cell lymphomas, only PET-positive individuals underwent randomization. PET-negative patients received CHOP. Patients with CD20-positive T-cell lymphomas also received rituximab.

PET-positive results

Of the PET-positive patients (108/862), 52 were randomized to receive 6 additional cycles of R-CHOP, and 56 were randomized to 6 cycles of the Burkitt protocol.

In general, survival rates were similar regardless of treatment. The 2-year overall survival (OS) rate was 63.6% for patients who received R-CHOP and 55.4% for those who received the more intensive protocol.

Two-year progression-free survival (PFS) rates were 49.4% and 43.1%, respectively. Two-year event-free survival (EFS) rates were 42.0% and 31.6%, respectively.

Among patients with diffuse large B-cell lymphoma (DLBCL), the OS rate was 64.8% for patients who received R-CHOP and 47.1% for those on the Burkitt protocol. PFS rates were 55.5% and 41.4%, respectively.

There was a significant difference in EFS rates among the DLBCL patients—52.4% in the R-CHOP arm and 28.3% in the intensive arm (P=0.0186).

Among T-cell lymphoma patients, the OS rate was 22.2% in the R-CHOP arm and 30.0% in the intensive arm. The PFS rates were 12.7% and 30%, respectively. The EFS rates were the same as the PFS rates.

Overall, patients who received the Burkitt protocol had significantly higher rates of grade 3/4 hematologic toxicities, infection, and mucositis.

PET-negative results

Of 754 PET-negative patients, 697 had CD20-positive lymphomas, and 255 of those patients (all with B-cell lymphomas) underwent randomization.

There were 129 patients who were randomized to receive 6 cycles of R-CHOP (2 before and 4 after randomization) and 126 who were randomized to receive 6 cycles of R-CHOP plus 2 additional cycles of rituximab.

Again, survival rates were similar regardless of treatment.

The 2-year OS was 88.2% for patients who received only R-CHOP and 87.2% for those with additional rituximab exposure. PFS rates were 82.0% and 77.5%, respectively. EFS rates were 76.4% and 73.5%, respectively.

In the DLBCL patients, the OS rate was 88.5% in the R-CHOP arm and 85.8% in the intensive arm. PFS rates were 82.3% and 77.7%, respectively. EFS rates were 72.6% and 78.9%, respectively.

As increasing the dose of rituximab did not improve outcomes, the investigators concluded that 6 cycles of R-CHOP should be the standard of care for these patients.

The team also said interim PET scanning is “a powerful tool” for identifying chemotherapy-resistant lymphomas, and PET-positive patients may be candidates for immunologic treatment approaches.

Image from Jens Langner

In the PETAL trial, treatment intensification based on results of an interim positron emission tomography (PET) scan did not improve survival outcomes for patients with aggressive lymphomas.

PET-positive patients did not benefit by switching from R-CHOP to a more intensive chemotherapy regimen.

PET-negative patients did not benefit from 2 additional cycles of rituximab after R-CHOP.

These results were published in the Journal of Clinical Oncology.

PETAL was a randomized trial of patients with newly diagnosed T- or B-cell lymphomas.

Patients received 2 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)—plus rituximab (R-CHOP) in CD20-positive lymphomas—followed by a PET scan.

PET-positive patients were randomized to receive 6 additional cycles of R-CHOP or 6 blocks of an intensive protocol used to treat Burkitt lymphoma. This protocol consisted of high-dose methotrexate, cytarabine, hyperfractionated cyclophosphamide and ifosfamide, split-dose doxorubicin and etoposide, vincristine, vindesine, and dexamethasone.

PET-negative patients with CD20-positive lymphomas were randomized to receive 4 additional cycles of R-CHOP or 4 additional cycles of R-CHOP followed by 2 more doses of rituximab.

Among patients with T-cell lymphomas, only PET-positive individuals underwent randomization. PET-negative patients received CHOP. Patients with CD20-positive T-cell lymphomas also received rituximab.

PET-positive results

Of the PET-positive patients (108/862), 52 were randomized to receive 6 additional cycles of R-CHOP, and 56 were randomized to 6 cycles of the Burkitt protocol.

In general, survival rates were similar regardless of treatment. The 2-year overall survival (OS) rate was 63.6% for patients who received R-CHOP and 55.4% for those who received the more intensive protocol.

Two-year progression-free survival (PFS) rates were 49.4% and 43.1%, respectively. Two-year event-free survival (EFS) rates were 42.0% and 31.6%, respectively.

Among patients with diffuse large B-cell lymphoma (DLBCL), the OS rate was 64.8% for patients who received R-CHOP and 47.1% for those on the Burkitt protocol. PFS rates were 55.5% and 41.4%, respectively.

There was a significant difference in EFS rates among the DLBCL patients—52.4% in the R-CHOP arm and 28.3% in the intensive arm (P=0.0186).

Among T-cell lymphoma patients, the OS rate was 22.2% in the R-CHOP arm and 30.0% in the intensive arm. The PFS rates were 12.7% and 30%, respectively. The EFS rates were the same as the PFS rates.

Overall, patients who received the Burkitt protocol had significantly higher rates of grade 3/4 hematologic toxicities, infection, and mucositis.

PET-negative results

Of 754 PET-negative patients, 697 had CD20-positive lymphomas, and 255 of those patients (all with B-cell lymphomas) underwent randomization.

There were 129 patients who were randomized to receive 6 cycles of R-CHOP (2 before and 4 after randomization) and 126 who were randomized to receive 6 cycles of R-CHOP plus 2 additional cycles of rituximab.

Again, survival rates were similar regardless of treatment.

The 2-year OS was 88.2% for patients who received only R-CHOP and 87.2% for those with additional rituximab exposure. PFS rates were 82.0% and 77.5%, respectively. EFS rates were 76.4% and 73.5%, respectively.

In the DLBCL patients, the OS rate was 88.5% in the R-CHOP arm and 85.8% in the intensive arm. PFS rates were 82.3% and 77.7%, respectively. EFS rates were 72.6% and 78.9%, respectively.

As increasing the dose of rituximab did not improve outcomes, the investigators concluded that 6 cycles of R-CHOP should be the standard of care for these patients.

The team also said interim PET scanning is “a powerful tool” for identifying chemotherapy-resistant lymphomas, and PET-positive patients may be candidates for immunologic treatment approaches.

Image from Jens Langner

In the PETAL trial, treatment intensification based on results of an interim positron emission tomography (PET) scan did not improve survival outcomes for patients with aggressive lymphomas.

PET-positive patients did not benefit by switching from R-CHOP to a more intensive chemotherapy regimen.

PET-negative patients did not benefit from 2 additional cycles of rituximab after R-CHOP.

These results were published in the Journal of Clinical Oncology.

PETAL was a randomized trial of patients with newly diagnosed T- or B-cell lymphomas.

Patients received 2 cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)—plus rituximab (R-CHOP) in CD20-positive lymphomas—followed by a PET scan.

PET-positive patients were randomized to receive 6 additional cycles of R-CHOP or 6 blocks of an intensive protocol used to treat Burkitt lymphoma. This protocol consisted of high-dose methotrexate, cytarabine, hyperfractionated cyclophosphamide and ifosfamide, split-dose doxorubicin and etoposide, vincristine, vindesine, and dexamethasone.

PET-negative patients with CD20-positive lymphomas were randomized to receive 4 additional cycles of R-CHOP or 4 additional cycles of R-CHOP followed by 2 more doses of rituximab.

Among patients with T-cell lymphomas, only PET-positive individuals underwent randomization. PET-negative patients received CHOP. Patients with CD20-positive T-cell lymphomas also received rituximab.

PET-positive results

Of the PET-positive patients (108/862), 52 were randomized to receive 6 additional cycles of R-CHOP, and 56 were randomized to 6 cycles of the Burkitt protocol.

In general, survival rates were similar regardless of treatment. The 2-year overall survival (OS) rate was 63.6% for patients who received R-CHOP and 55.4% for those who received the more intensive protocol.

Two-year progression-free survival (PFS) rates were 49.4% and 43.1%, respectively. Two-year event-free survival (EFS) rates were 42.0% and 31.6%, respectively.

Among patients with diffuse large B-cell lymphoma (DLBCL), the OS rate was 64.8% for patients who received R-CHOP and 47.1% for those on the Burkitt protocol. PFS rates were 55.5% and 41.4%, respectively.

There was a significant difference in EFS rates among the DLBCL patients—52.4% in the R-CHOP arm and 28.3% in the intensive arm (P=0.0186).

Among T-cell lymphoma patients, the OS rate was 22.2% in the R-CHOP arm and 30.0% in the intensive arm. The PFS rates were 12.7% and 30%, respectively. The EFS rates were the same as the PFS rates.

Overall, patients who received the Burkitt protocol had significantly higher rates of grade 3/4 hematologic toxicities, infection, and mucositis.

PET-negative results

Of 754 PET-negative patients, 697 had CD20-positive lymphomas, and 255 of those patients (all with B-cell lymphomas) underwent randomization.

There were 129 patients who were randomized to receive 6 cycles of R-CHOP (2 before and 4 after randomization) and 126 who were randomized to receive 6 cycles of R-CHOP plus 2 additional cycles of rituximab.

Again, survival rates were similar regardless of treatment.

The 2-year OS was 88.2% for patients who received only R-CHOP and 87.2% for those with additional rituximab exposure. PFS rates were 82.0% and 77.5%, respectively. EFS rates were 76.4% and 73.5%, respectively.

In the DLBCL patients, the OS rate was 88.5% in the R-CHOP arm and 85.8% in the intensive arm. PFS rates were 82.3% and 77.7%, respectively. EFS rates were 72.6% and 78.9%, respectively.

As increasing the dose of rituximab did not improve outcomes, the investigators concluded that 6 cycles of R-CHOP should be the standard of care for these patients.

The team also said interim PET scanning is “a powerful tool” for identifying chemotherapy-resistant lymphomas, and PET-positive patients may be candidates for immunologic treatment approaches.

Research Hospital

New research has shown that childhood cancer survivors (CCSs) with certain germline mutations have higher relative rates (RRs) of secondary neoplasms (SNs) later in life.

Mutation carriers had significantly higher rates of breast cancer and sarcoma if they had received radiation to treat their initial cancer.

Among CCSs who did not receive radiation, the mutations were associated with increased rates of any SN, breast cancer, nonmelanoma skin cancer, and 2 or more histologically distinct SNs.

These findings were reported in the Journal of Clinical Oncology.

Researchers sequenced samples from 3006 CCSs who were at least 5 years from their initial cancer diagnosis as well as 341 samples from cancer-free control subjects.

All subjects were participants in the St. Jude Lifetime Cohort Study, a retrospective study with prospective clinical follow-up.

Thirty-five percent of the CCSs had survived leukemia, and 19% had survived lymphoma.

The CCS’s median age at childhood cancer diagnosis was 7.1 years, and the median follow-up was 28 years. The controls had a median age of 36.4 at follow-up.

Results

There were 1120 SNs diagnosed in 439 CCSs (14.6%). Ninety-one CCSs developed 2 or more histologically distinct SNs. The median time to SN diagnosis was 25.6 years

Non-melanoma skin cancer (580 in 159 CCSs), meningiomas (233 in 102 CCSs), thyroid cancer (67 in 67 CCSs), and breast cancer (60 in 53 CCSs) were among the SNs reported.

There were 15 neoplasms recorded in the control group—14 cases of non-melanoma skin cancer and 1 meningioma.

Pathogenic or likely pathogenic (P/LP) mutations in 32 genes were reported in 175 CCSs. The prevalence in CCSs (5.8%) was nearly 10-fold higher than in controls (0.6%).

The most commonly mutated genes in CCSs were RB1 (n=43), NF1 (n=22), BRCA2 (n=14), BRCA1 (n=12), and TP53 (n=10).

In a multivariable analysis adjusted for sex, age at primary cancer diagnosis, and treatment, P/LP mutation carriers had a significantly higher rate of any SN (RR=1.8).

The rate of subsequent breast cancer was significantly increased among females with a P/LP mutation (RR= 9.4), recipients of chest radiation (RR=7.9), and those with higher anthracycline exposure (RR=2.4).

The rate of subsequent sarcoma was significantly increased for mutation carriers (RR=10.9) and CCSs with greater exposure to alkylating agents (RR=3.8).

Among irradiated CCSs, P/LP mutations were associated with significantly increased rates of breast cancer (RR=13.9) and sarcoma (RR=10.6)

Among non-irradiated CCSs, P/LP mutations were associated with significantly increased rates of any SN (RR=4.7), breast cancer (RR=7.7), nonmelanoma skin cancer (RR=11.0), and 2 or more histologically distinct SNs (RR=18.6).

The researchers said the higher risk of SNs in CCSs with P/LP mutations suggests all CCSs should be referred for genetic counseling.

Research Hospital

New research has shown that childhood cancer survivors (CCSs) with certain germline mutations have higher relative rates (RRs) of secondary neoplasms (SNs) later in life.

Mutation carriers had significantly higher rates of breast cancer and sarcoma if they had received radiation to treat their initial cancer.

Among CCSs who did not receive radiation, the mutations were associated with increased rates of any SN, breast cancer, nonmelanoma skin cancer, and 2 or more histologically distinct SNs.

These findings were reported in the Journal of Clinical Oncology.

Researchers sequenced samples from 3006 CCSs who were at least 5 years from their initial cancer diagnosis as well as 341 samples from cancer-free control subjects.

All subjects were participants in the St. Jude Lifetime Cohort Study, a retrospective study with prospective clinical follow-up.

Thirty-five percent of the CCSs had survived leukemia, and 19% had survived lymphoma.

The CCS’s median age at childhood cancer diagnosis was 7.1 years, and the median follow-up was 28 years. The controls had a median age of 36.4 at follow-up.

Results

There were 1120 SNs diagnosed in 439 CCSs (14.6%). Ninety-one CCSs developed 2 or more histologically distinct SNs. The median time to SN diagnosis was 25.6 years

Non-melanoma skin cancer (580 in 159 CCSs), meningiomas (233 in 102 CCSs), thyroid cancer (67 in 67 CCSs), and breast cancer (60 in 53 CCSs) were among the SNs reported.

There were 15 neoplasms recorded in the control group—14 cases of non-melanoma skin cancer and 1 meningioma.

Pathogenic or likely pathogenic (P/LP) mutations in 32 genes were reported in 175 CCSs. The prevalence in CCSs (5.8%) was nearly 10-fold higher than in controls (0.6%).

The most commonly mutated genes in CCSs were RB1 (n=43), NF1 (n=22), BRCA2 (n=14), BRCA1 (n=12), and TP53 (n=10).

In a multivariable analysis adjusted for sex, age at primary cancer diagnosis, and treatment, P/LP mutation carriers had a significantly higher rate of any SN (RR=1.8).

The rate of subsequent breast cancer was significantly increased among females with a P/LP mutation (RR= 9.4), recipients of chest radiation (RR=7.9), and those with higher anthracycline exposure (RR=2.4).

The rate of subsequent sarcoma was significantly increased for mutation carriers (RR=10.9) and CCSs with greater exposure to alkylating agents (RR=3.8).

Among irradiated CCSs, P/LP mutations were associated with significantly increased rates of breast cancer (RR=13.9) and sarcoma (RR=10.6)

Among non-irradiated CCSs, P/LP mutations were associated with significantly increased rates of any SN (RR=4.7), breast cancer (RR=7.7), nonmelanoma skin cancer (RR=11.0), and 2 or more histologically distinct SNs (RR=18.6).

The researchers said the higher risk of SNs in CCSs with P/LP mutations suggests all CCSs should be referred for genetic counseling.

Research Hospital

New research has shown that childhood cancer survivors (CCSs) with certain germline mutations have higher relative rates (RRs) of secondary neoplasms (SNs) later in life.

Mutation carriers had significantly higher rates of breast cancer and sarcoma if they had received radiation to treat their initial cancer.

Among CCSs who did not receive radiation, the mutations were associated with increased rates of any SN, breast cancer, nonmelanoma skin cancer, and 2 or more histologically distinct SNs.

These findings were reported in the Journal of Clinical Oncology.

Researchers sequenced samples from 3006 CCSs who were at least 5 years from their initial cancer diagnosis as well as 341 samples from cancer-free control subjects.

All subjects were participants in the St. Jude Lifetime Cohort Study, a retrospective study with prospective clinical follow-up.

Thirty-five percent of the CCSs had survived leukemia, and 19% had survived lymphoma.

The CCS’s median age at childhood cancer diagnosis was 7.1 years, and the median follow-up was 28 years. The controls had a median age of 36.4 at follow-up.

Results

There were 1120 SNs diagnosed in 439 CCSs (14.6%). Ninety-one CCSs developed 2 or more histologically distinct SNs. The median time to SN diagnosis was 25.6 years

Non-melanoma skin cancer (580 in 159 CCSs), meningiomas (233 in 102 CCSs), thyroid cancer (67 in 67 CCSs), and breast cancer (60 in 53 CCSs) were among the SNs reported.

There were 15 neoplasms recorded in the control group—14 cases of non-melanoma skin cancer and 1 meningioma.

Pathogenic or likely pathogenic (P/LP) mutations in 32 genes were reported in 175 CCSs. The prevalence in CCSs (5.8%) was nearly 10-fold higher than in controls (0.6%).

The most commonly mutated genes in CCSs were RB1 (n=43), NF1 (n=22), BRCA2 (n=14), BRCA1 (n=12), and TP53 (n=10).

In a multivariable analysis adjusted for sex, age at primary cancer diagnosis, and treatment, P/LP mutation carriers had a significantly higher rate of any SN (RR=1.8).

The rate of subsequent breast cancer was significantly increased among females with a P/LP mutation (RR= 9.4), recipients of chest radiation (RR=7.9), and those with higher anthracycline exposure (RR=2.4).

The rate of subsequent sarcoma was significantly increased for mutation carriers (RR=10.9) and CCSs with greater exposure to alkylating agents (RR=3.8).

Among irradiated CCSs, P/LP mutations were associated with significantly increased rates of breast cancer (RR=13.9) and sarcoma (RR=10.6)

Among non-irradiated CCSs, P/LP mutations were associated with significantly increased rates of any SN (RR=4.7), breast cancer (RR=7.7), nonmelanoma skin cancer (RR=11.0), and 2 or more histologically distinct SNs (RR=18.6).

The researchers said the higher risk of SNs in CCSs with P/LP mutations suggests all CCSs should be referred for genetic counseling.