Leukemia, Myelodysplasia, Transplantation

Photo by Tiffany D. Nicholson

Smoking by either parent helps promote genetic deletions in children that are associated with the development and progression of acute lymphoblastic leukemia (ALL), according to a study published in Cancer Research.

The strongest associations in this study were found in children whose parents smoked while the children were in utero and during their infancy.

However, the genetic deletions were also noted in the offspring of parents who may have quit smoking even before conception.

The link between ALL and parental smoking has already been established, but this is the first study that points to specific genetic changes in children with ALL, according to study author Adam de Smith, PhD, of the University of California San Francisco.

“With more smoking among the parents, we saw more deletions within the child’s ALL cells at diagnosis,” Dr de smith said.

For this study, he and his colleagues looked at pre-treatment tumor samples from 559 ALL patients.

The team wanted to see if any of the 8 genes that are frequently deleted in ALL patients (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) were missing in the samples.

Questionnaires were given to parents to find out if smoking habits impacted the number of genetic deletions. Data was corroborated by a biomarker in newborns’ blood samples that indicates exposure to maternal smoking during pregnancy.

The researchers found that approximately two-thirds of the tumor samples (n=353) contained at least 1 deletion.

Deletions were considerably more common in children whose mothers had smoked during pregnancy and after birth.

For each 5 cigarettes smoked daily during pregnancy, there was a 22% increase in the number of deletions. For each 5 cigarettes smoked daily during breastfeeding, there was a 74% increase in the number of deletions.

Smoking of 5 cigarettes daily by the mother or father before conception was associated with a 7% to 8% higher number of deletions.

Role of child age and sex

One discovery the researchers found intriguing was the link between the fathers’ pre-conception smoking and their child’s age at diagnosis.

“There was a significant effect on deletion numbers in cases where the patient was age 6 or younger,” Dr de Smith said. “Our results suggest that paternal pre-conception smoking, which is known to cause oxidative damage to sperm DNA, may lead to a higher propensity of deletions in children with earlier-onset ALL.”

“It is also true that some of those fathers who smoked before conception also continue to smoke in the presence of the mother and child, so more research is needed to explain the mechanism of smoking-related damage in all of the time periods of exposure to the child.”

In addition, male children were found to be more sensitive to the effects of maternal smoking, including smoking that occurred pre-conception.

The researchers said this could be explained by the fact that male fetuses grow more rapidly, which leads to increased vulnerability of developing lymphocytes to toxins that cause genetic damage.

“Our study indicates that the more tobacco exposure, the more cumulative DNA damage is evident in the ALL cell,” said study author Joseph Wiemels, PhD, of the University of California San Francisco.

“While causes of ALL are multifactorial—including the inborn genetic makeup of the child, patterns of infection, pesticides, and other environmental exposure—if there was no smoking in the environment, then there would likely be fewer children with the disease. We may add ALL to the long list of diseases impacted by smoking, and, in this case, affecting one of our most vulnerable populations—our children.”

Photo by Tiffany D. Nicholson

Smoking by either parent helps promote genetic deletions in children that are associated with the development and progression of acute lymphoblastic leukemia (ALL), according to a study published in Cancer Research.

The strongest associations in this study were found in children whose parents smoked while the children were in utero and during their infancy.

However, the genetic deletions were also noted in the offspring of parents who may have quit smoking even before conception.

The link between ALL and parental smoking has already been established, but this is the first study that points to specific genetic changes in children with ALL, according to study author Adam de Smith, PhD, of the University of California San Francisco.

“With more smoking among the parents, we saw more deletions within the child’s ALL cells at diagnosis,” Dr de smith said.

For this study, he and his colleagues looked at pre-treatment tumor samples from 559 ALL patients.

The team wanted to see if any of the 8 genes that are frequently deleted in ALL patients (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) were missing in the samples.

Questionnaires were given to parents to find out if smoking habits impacted the number of genetic deletions. Data was corroborated by a biomarker in newborns’ blood samples that indicates exposure to maternal smoking during pregnancy.

The researchers found that approximately two-thirds of the tumor samples (n=353) contained at least 1 deletion.

Deletions were considerably more common in children whose mothers had smoked during pregnancy and after birth.

For each 5 cigarettes smoked daily during pregnancy, there was a 22% increase in the number of deletions. For each 5 cigarettes smoked daily during breastfeeding, there was a 74% increase in the number of deletions.

Smoking of 5 cigarettes daily by the mother or father before conception was associated with a 7% to 8% higher number of deletions.

Role of child age and sex

One discovery the researchers found intriguing was the link between the fathers’ pre-conception smoking and their child’s age at diagnosis.

“There was a significant effect on deletion numbers in cases where the patient was age 6 or younger,” Dr de Smith said. “Our results suggest that paternal pre-conception smoking, which is known to cause oxidative damage to sperm DNA, may lead to a higher propensity of deletions in children with earlier-onset ALL.”

“It is also true that some of those fathers who smoked before conception also continue to smoke in the presence of the mother and child, so more research is needed to explain the mechanism of smoking-related damage in all of the time periods of exposure to the child.”

In addition, male children were found to be more sensitive to the effects of maternal smoking, including smoking that occurred pre-conception.

The researchers said this could be explained by the fact that male fetuses grow more rapidly, which leads to increased vulnerability of developing lymphocytes to toxins that cause genetic damage.

“Our study indicates that the more tobacco exposure, the more cumulative DNA damage is evident in the ALL cell,” said study author Joseph Wiemels, PhD, of the University of California San Francisco.

“While causes of ALL are multifactorial—including the inborn genetic makeup of the child, patterns of infection, pesticides, and other environmental exposure—if there was no smoking in the environment, then there would likely be fewer children with the disease. We may add ALL to the long list of diseases impacted by smoking, and, in this case, affecting one of our most vulnerable populations—our children.”

Photo by Tiffany D. Nicholson

Smoking by either parent helps promote genetic deletions in children that are associated with the development and progression of acute lymphoblastic leukemia (ALL), according to a study published in Cancer Research.

The strongest associations in this study were found in children whose parents smoked while the children were in utero and during their infancy.

However, the genetic deletions were also noted in the offspring of parents who may have quit smoking even before conception.

The link between ALL and parental smoking has already been established, but this is the first study that points to specific genetic changes in children with ALL, according to study author Adam de Smith, PhD, of the University of California San Francisco.

“With more smoking among the parents, we saw more deletions within the child’s ALL cells at diagnosis,” Dr de smith said.

For this study, he and his colleagues looked at pre-treatment tumor samples from 559 ALL patients.

The team wanted to see if any of the 8 genes that are frequently deleted in ALL patients (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) were missing in the samples.

Questionnaires were given to parents to find out if smoking habits impacted the number of genetic deletions. Data was corroborated by a biomarker in newborns’ blood samples that indicates exposure to maternal smoking during pregnancy.

The researchers found that approximately two-thirds of the tumor samples (n=353) contained at least 1 deletion.

Deletions were considerably more common in children whose mothers had smoked during pregnancy and after birth.

For each 5 cigarettes smoked daily during pregnancy, there was a 22% increase in the number of deletions. For each 5 cigarettes smoked daily during breastfeeding, there was a 74% increase in the number of deletions.

Smoking of 5 cigarettes daily by the mother or father before conception was associated with a 7% to 8% higher number of deletions.

Role of child age and sex

One discovery the researchers found intriguing was the link between the fathers’ pre-conception smoking and their child’s age at diagnosis.

“There was a significant effect on deletion numbers in cases where the patient was age 6 or younger,” Dr de Smith said. “Our results suggest that paternal pre-conception smoking, which is known to cause oxidative damage to sperm DNA, may lead to a higher propensity of deletions in children with earlier-onset ALL.”

“It is also true that some of those fathers who smoked before conception also continue to smoke in the presence of the mother and child, so more research is needed to explain the mechanism of smoking-related damage in all of the time periods of exposure to the child.”

In addition, male children were found to be more sensitive to the effects of maternal smoking, including smoking that occurred pre-conception.

The researchers said this could be explained by the fact that male fetuses grow more rapidly, which leads to increased vulnerability of developing lymphocytes to toxins that cause genetic damage.

“Our study indicates that the more tobacco exposure, the more cumulative DNA damage is evident in the ALL cell,” said study author Joseph Wiemels, PhD, of the University of California San Francisco.

“While causes of ALL are multifactorial—including the inborn genetic makeup of the child, patterns of infection, pesticides, and other environmental exposure—if there was no smoking in the environment, then there would likely be fewer children with the disease. We may add ALL to the long list of diseases impacted by smoking, and, in this case, affecting one of our most vulnerable populations—our children.”

ORLANDO – For patients who have received hematopoietic cell transplants, a rhinovirus infection can become much more than a cold.

“It holds true that rhinovirus is just as likely to be associated with mortality as are other respiratory viruses” among HCT recipients, Alpana Waghmare, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

In a new retrospective study, Dr. Waghmare and her coinvestigators found that the median time for a rhinovirus infection to progress from an upper to a lower respiratory tract infection was about 2 weeks among post-HCT patients.

Clinical and demographic risk factors for progression to lower respiratory tract infection included higher levels of steroid use (2 mg/kg per day or more) before developing the upper respiratory infection, a low white blood cell count, and a low monocyte count, said Dr. Waghmare, an infectious disease specialist and professor of pediatrics at the University of Washington, Seattle.

Of 3,445 HCT patients treated at the university center during the 6-year study, 732 patients (21%) were positive for human rhinovirus. Patients were classified as having upper respiratory infections if they had a PCR-positive nasal swab.

Patients were classed in one of three categories for potential lower respiratory infections: Proven lower respiratory infections were those detected by bronchoalveolar lavage or biopsy in patients who had a new radiographic abnormality. Probable lower respiratory infections were those with positive findings on bronchoalveolar lavage or biopsy but without radiographic changes. In possible lower respiratory infections, patients had upper tract virus detected on nasal swabs but did have a new radiographic abnormality.

Among the patients positive for human rhinovirus, 85% (665 patients) presented with upper respiratory infections and 15% (117 patients) with lower respiratory tract infections. By day 90, 16% of patients progressed from upper to lower respiratory tract infections. The median time to progression was 13.5 days. Progression to proven lower respiratory tract infection affected 5% of the HCT recipients.

In multivariable analytic models, a minimum white blood cell count of 1,000 or less was associated with a hazard ratio (HR) of 2.21 for progression to lower respiratory tract infection. A minimum monocyte count of 1,000 or less was associated with a HR of 3.66 for progression to lower respiratory tract infection.

The model also found a HR of 3.37 for lower respiratory tract infection with steroid use of 2 mg/kg per day or more. The patient’s conditioning regimen and donor type were not significantly associated with risk of progression to lower respiratory infection.

Viral copathogens, prior respiratory virus episodes, and the duration of time since HCT were not associated with risk of progress to lower respiratory infections. Neither were patient age, baseline lung function, and the year the transplant occurred.

“These data provide an initial framework for patient risk stratification and the development of rational prevention and treatment strategies in HCT recipients,” she said.

Dr. Waghmare reported receiving research funding from Aviragen, the maker of vapendavir, an investigational drug for human rhinovirus infection, and Gilead Sciences.

[email protected]

On Twitter @karioakes

ORLANDO – For patients who have received hematopoietic cell transplants, a rhinovirus infection can become much more than a cold.

“It holds true that rhinovirus is just as likely to be associated with mortality as are other respiratory viruses” among HCT recipients, Alpana Waghmare, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

In a new retrospective study, Dr. Waghmare and her coinvestigators found that the median time for a rhinovirus infection to progress from an upper to a lower respiratory tract infection was about 2 weeks among post-HCT patients.

Clinical and demographic risk factors for progression to lower respiratory tract infection included higher levels of steroid use (2 mg/kg per day or more) before developing the upper respiratory infection, a low white blood cell count, and a low monocyte count, said Dr. Waghmare, an infectious disease specialist and professor of pediatrics at the University of Washington, Seattle.

Of 3,445 HCT patients treated at the university center during the 6-year study, 732 patients (21%) were positive for human rhinovirus. Patients were classified as having upper respiratory infections if they had a PCR-positive nasal swab.

Patients were classed in one of three categories for potential lower respiratory infections: Proven lower respiratory infections were those detected by bronchoalveolar lavage or biopsy in patients who had a new radiographic abnormality. Probable lower respiratory infections were those with positive findings on bronchoalveolar lavage or biopsy but without radiographic changes. In possible lower respiratory infections, patients had upper tract virus detected on nasal swabs but did have a new radiographic abnormality.

Among the patients positive for human rhinovirus, 85% (665 patients) presented with upper respiratory infections and 15% (117 patients) with lower respiratory tract infections. By day 90, 16% of patients progressed from upper to lower respiratory tract infections. The median time to progression was 13.5 days. Progression to proven lower respiratory tract infection affected 5% of the HCT recipients.

In multivariable analytic models, a minimum white blood cell count of 1,000 or less was associated with a hazard ratio (HR) of 2.21 for progression to lower respiratory tract infection. A minimum monocyte count of 1,000 or less was associated with a HR of 3.66 for progression to lower respiratory tract infection.

The model also found a HR of 3.37 for lower respiratory tract infection with steroid use of 2 mg/kg per day or more. The patient’s conditioning regimen and donor type were not significantly associated with risk of progression to lower respiratory infection.

Viral copathogens, prior respiratory virus episodes, and the duration of time since HCT were not associated with risk of progress to lower respiratory infections. Neither were patient age, baseline lung function, and the year the transplant occurred.

“These data provide an initial framework for patient risk stratification and the development of rational prevention and treatment strategies in HCT recipients,” she said.

Dr. Waghmare reported receiving research funding from Aviragen, the maker of vapendavir, an investigational drug for human rhinovirus infection, and Gilead Sciences.

[email protected]

On Twitter @karioakes

ORLANDO – For patients who have received hematopoietic cell transplants, a rhinovirus infection can become much more than a cold.

“It holds true that rhinovirus is just as likely to be associated with mortality as are other respiratory viruses” among HCT recipients, Alpana Waghmare, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

In a new retrospective study, Dr. Waghmare and her coinvestigators found that the median time for a rhinovirus infection to progress from an upper to a lower respiratory tract infection was about 2 weeks among post-HCT patients.

Clinical and demographic risk factors for progression to lower respiratory tract infection included higher levels of steroid use (2 mg/kg per day or more) before developing the upper respiratory infection, a low white blood cell count, and a low monocyte count, said Dr. Waghmare, an infectious disease specialist and professor of pediatrics at the University of Washington, Seattle.

Of 3,445 HCT patients treated at the university center during the 6-year study, 732 patients (21%) were positive for human rhinovirus. Patients were classified as having upper respiratory infections if they had a PCR-positive nasal swab.

Patients were classed in one of three categories for potential lower respiratory infections: Proven lower respiratory infections were those detected by bronchoalveolar lavage or biopsy in patients who had a new radiographic abnormality. Probable lower respiratory infections were those with positive findings on bronchoalveolar lavage or biopsy but without radiographic changes. In possible lower respiratory infections, patients had upper tract virus detected on nasal swabs but did have a new radiographic abnormality.

Among the patients positive for human rhinovirus, 85% (665 patients) presented with upper respiratory infections and 15% (117 patients) with lower respiratory tract infections. By day 90, 16% of patients progressed from upper to lower respiratory tract infections. The median time to progression was 13.5 days. Progression to proven lower respiratory tract infection affected 5% of the HCT recipients.

In multivariable analytic models, a minimum white blood cell count of 1,000 or less was associated with a hazard ratio (HR) of 2.21 for progression to lower respiratory tract infection. A minimum monocyte count of 1,000 or less was associated with a HR of 3.66 for progression to lower respiratory tract infection.

The model also found a HR of 3.37 for lower respiratory tract infection with steroid use of 2 mg/kg per day or more. The patient’s conditioning regimen and donor type were not significantly associated with risk of progression to lower respiratory infection.

Viral copathogens, prior respiratory virus episodes, and the duration of time since HCT were not associated with risk of progress to lower respiratory infections. Neither were patient age, baseline lung function, and the year the transplant occurred.

“These data provide an initial framework for patient risk stratification and the development of rational prevention and treatment strategies in HCT recipients,” she said.

Dr. Waghmare reported receiving research funding from Aviragen, the maker of vapendavir, an investigational drug for human rhinovirus infection, and Gilead Sciences.

[email protected]

On Twitter @karioakes

NEW YORK – The success that tyrosine kinase inhibitors have had in prolonging life and producing deep hematologic and molecular remissions in patients with chronic myeloid leukemia has led to an unexpected bonus for young women living with the disease: an opportunity to safely become pregnant and mother a child.

The approach is not yet routine and poses a level of risk to both the mother and fetus, especially because tyrosine kinase inhibitors (TKIs) are teratogenic. But with careful planning, close gestational monitoring, and with support from skilled obstetricians, the scenario of a successful pregnancy in women with chronic myeloid leukemia (CML) has now played out several dozen times at a handful of U.S. centers, Mrinal S. Patnaik, MD, said in a talk at the conference held by Imedex.

“We make it clear that this is experimental and is associated with risk, and we share the data [from case reports]; but if the woman wants to go forward,” a protocol now exists “to successfully get them to pregnancy,” said Dr. Patnaik, a hematologist oncologist at the Mayo Clinic in Rochester, Minn.

At Mayo alone, upwards of 20 women with CML have been successfully shepherded through pregnancy, he said in a video interview.

The prospect for a planned pregnancy is reserved for women with their CML well controlled for at least 2 years using a TKI, most often imatinib (Gleevec). In addition to being under complete hematologic control, the candidate patient must also show a deep molecular response, which means a blood level of the BRC-ABL tyrosine kinase that drives CML at least 4 or 4.5 logs (10,000-50,000-fold) below pretreatment levels or molecularly undetectable.

The patient then monitors her ovulatory cycle and stops her medication at the time of ovulation, attempts conception, and then monitors whether pregnancy has actually started. If it has, she needs to stay off her TKI regimen through at least the first 18 weeks of gestation, although an even longer drug holiday is preferred. If not, she resumes the medication and repeats the process later if she wants.

Once the women is pregnant and remains off her TKI regimen Dr. Patnaik and his associates closely follow the woman for signs of a molecular or hematologic relapse, although the latter are unusual. If a resurgence of CML stem cells occurs, the woman receives treatment with pegylated interferon-alpha, which is safe during pregnancy. When possible, TKI treatment remains on hold into the breast-feeding period.

During pregnancy and delivery, the patient requires careful and regular follow-up by a maternal-fetal medicine specialist and has an ongoing risk for high platelet counts causing placental blood clots, fetuses that are small for gestational age, preterm labor, premature rupture of membranes, and other complications.

“These are manageable with good obstetrical care,” Dr. Patnaik said. “We have developed a good system to work out the obstetrical complications.

“By and large we can be successful, but it requires a lot of monitoring and a lot of patient compliance with regular follow-ups,” he stressed.

In a video interview at the meeting, Dr. Patnaik discussed the approach he takes with his patients.

[email protected]

On Twitter @mitchelzoler

NEW YORK – The success that tyrosine kinase inhibitors have had in prolonging life and producing deep hematologic and molecular remissions in patients with chronic myeloid leukemia has led to an unexpected bonus for young women living with the disease: an opportunity to safely become pregnant and mother a child.

The approach is not yet routine and poses a level of risk to both the mother and fetus, especially because tyrosine kinase inhibitors (TKIs) are teratogenic. But with careful planning, close gestational monitoring, and with support from skilled obstetricians, the scenario of a successful pregnancy in women with chronic myeloid leukemia (CML) has now played out several dozen times at a handful of U.S. centers, Mrinal S. Patnaik, MD, said in a talk at the conference held by Imedex.

“We make it clear that this is experimental and is associated with risk, and we share the data [from case reports]; but if the woman wants to go forward,” a protocol now exists “to successfully get them to pregnancy,” said Dr. Patnaik, a hematologist oncologist at the Mayo Clinic in Rochester, Minn.

At Mayo alone, upwards of 20 women with CML have been successfully shepherded through pregnancy, he said in a video interview.

The prospect for a planned pregnancy is reserved for women with their CML well controlled for at least 2 years using a TKI, most often imatinib (Gleevec). In addition to being under complete hematologic control, the candidate patient must also show a deep molecular response, which means a blood level of the BRC-ABL tyrosine kinase that drives CML at least 4 or 4.5 logs (10,000-50,000-fold) below pretreatment levels or molecularly undetectable.

The patient then monitors her ovulatory cycle and stops her medication at the time of ovulation, attempts conception, and then monitors whether pregnancy has actually started. If it has, she needs to stay off her TKI regimen through at least the first 18 weeks of gestation, although an even longer drug holiday is preferred. If not, she resumes the medication and repeats the process later if she wants.

Once the women is pregnant and remains off her TKI regimen Dr. Patnaik and his associates closely follow the woman for signs of a molecular or hematologic relapse, although the latter are unusual. If a resurgence of CML stem cells occurs, the woman receives treatment with pegylated interferon-alpha, which is safe during pregnancy. When possible, TKI treatment remains on hold into the breast-feeding period.

During pregnancy and delivery, the patient requires careful and regular follow-up by a maternal-fetal medicine specialist and has an ongoing risk for high platelet counts causing placental blood clots, fetuses that are small for gestational age, preterm labor, premature rupture of membranes, and other complications.

“These are manageable with good obstetrical care,” Dr. Patnaik said. “We have developed a good system to work out the obstetrical complications.

“By and large we can be successful, but it requires a lot of monitoring and a lot of patient compliance with regular follow-ups,” he stressed.

In a video interview at the meeting, Dr. Patnaik discussed the approach he takes with his patients.

[email protected]

On Twitter @mitchelzoler

NEW YORK – The success that tyrosine kinase inhibitors have had in prolonging life and producing deep hematologic and molecular remissions in patients with chronic myeloid leukemia has led to an unexpected bonus for young women living with the disease: an opportunity to safely become pregnant and mother a child.

The approach is not yet routine and poses a level of risk to both the mother and fetus, especially because tyrosine kinase inhibitors (TKIs) are teratogenic. But with careful planning, close gestational monitoring, and with support from skilled obstetricians, the scenario of a successful pregnancy in women with chronic myeloid leukemia (CML) has now played out several dozen times at a handful of U.S. centers, Mrinal S. Patnaik, MD, said in a talk at the conference held by Imedex.

“We make it clear that this is experimental and is associated with risk, and we share the data [from case reports]; but if the woman wants to go forward,” a protocol now exists “to successfully get them to pregnancy,” said Dr. Patnaik, a hematologist oncologist at the Mayo Clinic in Rochester, Minn.

At Mayo alone, upwards of 20 women with CML have been successfully shepherded through pregnancy, he said in a video interview.

The prospect for a planned pregnancy is reserved for women with their CML well controlled for at least 2 years using a TKI, most often imatinib (Gleevec). In addition to being under complete hematologic control, the candidate patient must also show a deep molecular response, which means a blood level of the BRC-ABL tyrosine kinase that drives CML at least 4 or 4.5 logs (10,000-50,000-fold) below pretreatment levels or molecularly undetectable.

The patient then monitors her ovulatory cycle and stops her medication at the time of ovulation, attempts conception, and then monitors whether pregnancy has actually started. If it has, she needs to stay off her TKI regimen through at least the first 18 weeks of gestation, although an even longer drug holiday is preferred. If not, she resumes the medication and repeats the process later if she wants.

Once the women is pregnant and remains off her TKI regimen Dr. Patnaik and his associates closely follow the woman for signs of a molecular or hematologic relapse, although the latter are unusual. If a resurgence of CML stem cells occurs, the woman receives treatment with pegylated interferon-alpha, which is safe during pregnancy. When possible, TKI treatment remains on hold into the breast-feeding period.

During pregnancy and delivery, the patient requires careful and regular follow-up by a maternal-fetal medicine specialist and has an ongoing risk for high platelet counts causing placental blood clots, fetuses that are small for gestational age, preterm labor, premature rupture of membranes, and other complications.

“These are manageable with good obstetrical care,” Dr. Patnaik said. “We have developed a good system to work out the obstetrical complications.

“By and large we can be successful, but it requires a lot of monitoring and a lot of patient compliance with regular follow-ups,” he stressed.

In a video interview at the meeting, Dr. Patnaik discussed the approach he takes with his patients.

[email protected]

On Twitter @mitchelzoler

ORLANDO – Ruxolitinib is currently the only drug approved for the treatment of myelofibrosis, but a number of other therapies are in clinical trials and showing promise, according to Ruben A. Mesa, MD.

“Our field ... is rapidly in evolution,” he said at the annual conference of the National Comprehensive Cancer Network, adding that efforts are underway to determine where these drugs might fit in.

Sharon Worcester/Frontline Medical News

Pacritinib

This JAK2/FT3 inhibitor reduces splenomegaly and its related symptoms, but may also help patients who have low platelet counts and a worse prognosis. Pacritinib has demonstrated safety in that population, said Dr. Mesa of Mayo Clinic Cancer Center, Phoenix, Ariz.

Concerns about increased mortality related to risk of intracranial hemorrhage and cardiovascular events led the Food and Drug Administration to place a full clinical hold on pacritinib in February 2016. That hold was lifted in January 2017 when data from the randomized, controlled, phase III PERSIST-2 study, as presented at the American Society of Hematology annual meeting in December 2016, showed the risks did not hold up among study patients.

PERSIST-2 compared pacritinib doses of 400 mg once daily and 200 mg twice daily with best alternative therapy, which was ruxolitinib in most patients, Dr. Mesa said. He noted that the study included patients who had marked thrombocytopenia and were allowed prior JAK2 inhibitor exposure.

The 200-mg twice-daily dosing was superior in achieving spleen volume reductions greater than 35%: 22% of patients in the 200-mg dosing group vs. 15% in the 400-mg once-daily dosing group, compared with 3% of those receiving best available therapy. The twice-daily dosing group also experienced greater symptom improvement: Thirty-two percent in the 200-mg twice-daily group vs. 17% in the 400-mg once-daily group achieved at least a 50% reduction in total symptom scale scores, compared with 14% of those receiving best available therapy.

Additional studies of pacritinib will begin enrolling soon, Dr. Mesa said, noting that these studies will look at lower doses in an effort to identify the minimally effective dose with the optimal balance of safety and efficacy.

Momelotinib

Momelotinib, a JAK1/JAK2 inhibitor, was evaluated in two large recently concluded phase III trials (SIMPLIFY-1 and SIMPLIFY-2). SIMPIFY-1 compared momelotinib to ruxolitinib in the front-line setting, and showed momelotinib to be noninferior for reducing splenomegaly.

“However, it was inferior for improvement in the symptom burden,” Dr. Mesa said, noting that while there seemed to be a favorable difference in terms of anemia, the study was structured in such a way that the agent needed to be noninferior for both spleen and symptoms for the anemia response to be evaluable.

SIMPLIFY-2 evaluated momelotinib in patients who had not responded to ruxolitinib. In this second-line setting, momelotinib was not superior to the best alternative therapy, but since the vast majority of the ruxolitinib failure patients remained on ruxolitinib, it is “a bit of a confounded study to assess,” he said.

The top-line data from these studies were issued in a press release from the manufacturer (Gilead) in November 2016, and the complete results are expected to be made public in the near future, at which time more will be known about the next steps for momelotinib, he said.

If approved, pacritinib and momelotinib could ultimately be positioned as a front-line and/or second-line treatment for myelofibrosis, Dr. Mesa predicted.

There has been a goal, in terms of trial design, to see if there is a niche for these drugs in the front-line setting based on blood counts.

“Those recommendations would clearly be very much dependent on the risk, the safety, and the efficacy,” he said.

PRM-151

This antifibrosing agent was shown to be active in early-phase trials – including in stage 1 of an adaptive phase II trial. PRM-151 is currently being evaluated in the fully-accrued ongoing phase II PROMOTE study to determine whether it improves splenomegaly, symptoms, and cytopenia. The primary endpoint of the study is the bone marrow response rate. Study subjects are patients with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis, and grade 2-3 fibrosis, said Dr. Mesa, who is the principal investigator for the study.

Imetelstat

This telomerase inhibitor is being evaluated in the randomized, multicenter, phase II IMbark study, designed to assess spleen volume and total symptom score as primary end points. Earlier studies have shown deep responses in patients with myelofibrosis who were treated with imetelstat, Dr. Mesa said.

The IMbark study (NCT02426086) was originally designed to evaluate two dosing regimens administered as a single agent to participants with intermediate-2 or high-risk myelofibrosis who were refractory to or relapsed after JAK inhibitor treatment. Participants received either 9.4 mg/kg or 4.7 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or study end.

According to information from Geron, which is developing the agent, enrollment of new participants is currently suspended following a planned internal data review, but enrollment “may be resumed after a second internal data review that is planned by the end of the second quarter of 2017.” If resumed, enrollment would be only to the higher-dose treatment arm; patients initially randomized to that arm may continue treatment, and those randomized to the lower-dose arm may see their dose increased at the investigator’s discretion.

If approved, PRM-151 and imetelstat would likely be positioned as second-line treatments for myelofibrosis, Dr. Mesa said, noting that determining which patients would be most likely to benefit from treatment with these agents would require a close look at the evidence from second-line studies.

Combination therapies

In addition to these investigational treatments, nearly 20 different combination treatments involving ruxolitinib plus another agent have been looked at to try to further improve activity. Some improvements in splenomegaly have been seen with combinations including ruxolitinib and either panobinostat (a histone deacytelase inhibitor), LDE225 (a hedgehog signaling pathway inhibitor), and BKM120 (a PI3-kinase inhibitor), he noted.

“For the area of greatest interest – which was to see incremental improvements in thrombocytopenia, anemia, or fibrosis – there have been favorable data, but they have been modest. It’s not quite clear that there is a combination that is ready for prime time, nor is there yet a combination that we have recommended through the treatment guidelines to be utilized for these patients,” he said.

Dr. Mesa has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals; Celgene Corporation, CTI BioPharma, the maker of pacritinib; Galena Biopharma; Gilead, the maker of momelotinib; Incyte, the maker of ruxolitinib; Novartis, the maker of panobinostat and BKM120; and Promedior, the maker of PRM-151.

[email protected]

ORLANDO – Ruxolitinib is currently the only drug approved for the treatment of myelofibrosis, but a number of other therapies are in clinical trials and showing promise, according to Ruben A. Mesa, MD.

“Our field ... is rapidly in evolution,” he said at the annual conference of the National Comprehensive Cancer Network, adding that efforts are underway to determine where these drugs might fit in.

Sharon Worcester/Frontline Medical News

Pacritinib

This JAK2/FT3 inhibitor reduces splenomegaly and its related symptoms, but may also help patients who have low platelet counts and a worse prognosis. Pacritinib has demonstrated safety in that population, said Dr. Mesa of Mayo Clinic Cancer Center, Phoenix, Ariz.

Concerns about increased mortality related to risk of intracranial hemorrhage and cardiovascular events led the Food and Drug Administration to place a full clinical hold on pacritinib in February 2016. That hold was lifted in January 2017 when data from the randomized, controlled, phase III PERSIST-2 study, as presented at the American Society of Hematology annual meeting in December 2016, showed the risks did not hold up among study patients.

PERSIST-2 compared pacritinib doses of 400 mg once daily and 200 mg twice daily with best alternative therapy, which was ruxolitinib in most patients, Dr. Mesa said. He noted that the study included patients who had marked thrombocytopenia and were allowed prior JAK2 inhibitor exposure.

The 200-mg twice-daily dosing was superior in achieving spleen volume reductions greater than 35%: 22% of patients in the 200-mg dosing group vs. 15% in the 400-mg once-daily dosing group, compared with 3% of those receiving best available therapy. The twice-daily dosing group also experienced greater symptom improvement: Thirty-two percent in the 200-mg twice-daily group vs. 17% in the 400-mg once-daily group achieved at least a 50% reduction in total symptom scale scores, compared with 14% of those receiving best available therapy.

Additional studies of pacritinib will begin enrolling soon, Dr. Mesa said, noting that these studies will look at lower doses in an effort to identify the minimally effective dose with the optimal balance of safety and efficacy.

Momelotinib

Momelotinib, a JAK1/JAK2 inhibitor, was evaluated in two large recently concluded phase III trials (SIMPLIFY-1 and SIMPLIFY-2). SIMPIFY-1 compared momelotinib to ruxolitinib in the front-line setting, and showed momelotinib to be noninferior for reducing splenomegaly.

“However, it was inferior for improvement in the symptom burden,” Dr. Mesa said, noting that while there seemed to be a favorable difference in terms of anemia, the study was structured in such a way that the agent needed to be noninferior for both spleen and symptoms for the anemia response to be evaluable.

SIMPLIFY-2 evaluated momelotinib in patients who had not responded to ruxolitinib. In this second-line setting, momelotinib was not superior to the best alternative therapy, but since the vast majority of the ruxolitinib failure patients remained on ruxolitinib, it is “a bit of a confounded study to assess,” he said.

The top-line data from these studies were issued in a press release from the manufacturer (Gilead) in November 2016, and the complete results are expected to be made public in the near future, at which time more will be known about the next steps for momelotinib, he said.

If approved, pacritinib and momelotinib could ultimately be positioned as a front-line and/or second-line treatment for myelofibrosis, Dr. Mesa predicted.

There has been a goal, in terms of trial design, to see if there is a niche for these drugs in the front-line setting based on blood counts.

“Those recommendations would clearly be very much dependent on the risk, the safety, and the efficacy,” he said.

PRM-151

This antifibrosing agent was shown to be active in early-phase trials – including in stage 1 of an adaptive phase II trial. PRM-151 is currently being evaluated in the fully-accrued ongoing phase II PROMOTE study to determine whether it improves splenomegaly, symptoms, and cytopenia. The primary endpoint of the study is the bone marrow response rate. Study subjects are patients with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis, and grade 2-3 fibrosis, said Dr. Mesa, who is the principal investigator for the study.

Imetelstat

This telomerase inhibitor is being evaluated in the randomized, multicenter, phase II IMbark study, designed to assess spleen volume and total symptom score as primary end points. Earlier studies have shown deep responses in patients with myelofibrosis who were treated with imetelstat, Dr. Mesa said.

The IMbark study (NCT02426086) was originally designed to evaluate two dosing regimens administered as a single agent to participants with intermediate-2 or high-risk myelofibrosis who were refractory to or relapsed after JAK inhibitor treatment. Participants received either 9.4 mg/kg or 4.7 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or study end.

According to information from Geron, which is developing the agent, enrollment of new participants is currently suspended following a planned internal data review, but enrollment “may be resumed after a second internal data review that is planned by the end of the second quarter of 2017.” If resumed, enrollment would be only to the higher-dose treatment arm; patients initially randomized to that arm may continue treatment, and those randomized to the lower-dose arm may see their dose increased at the investigator’s discretion.

If approved, PRM-151 and imetelstat would likely be positioned as second-line treatments for myelofibrosis, Dr. Mesa said, noting that determining which patients would be most likely to benefit from treatment with these agents would require a close look at the evidence from second-line studies.

Combination therapies

In addition to these investigational treatments, nearly 20 different combination treatments involving ruxolitinib plus another agent have been looked at to try to further improve activity. Some improvements in splenomegaly have been seen with combinations including ruxolitinib and either panobinostat (a histone deacytelase inhibitor), LDE225 (a hedgehog signaling pathway inhibitor), and BKM120 (a PI3-kinase inhibitor), he noted.

“For the area of greatest interest – which was to see incremental improvements in thrombocytopenia, anemia, or fibrosis – there have been favorable data, but they have been modest. It’s not quite clear that there is a combination that is ready for prime time, nor is there yet a combination that we have recommended through the treatment guidelines to be utilized for these patients,” he said.

Dr. Mesa has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals; Celgene Corporation, CTI BioPharma, the maker of pacritinib; Galena Biopharma; Gilead, the maker of momelotinib; Incyte, the maker of ruxolitinib; Novartis, the maker of panobinostat and BKM120; and Promedior, the maker of PRM-151.

[email protected]

ORLANDO – Ruxolitinib is currently the only drug approved for the treatment of myelofibrosis, but a number of other therapies are in clinical trials and showing promise, according to Ruben A. Mesa, MD.

“Our field ... is rapidly in evolution,” he said at the annual conference of the National Comprehensive Cancer Network, adding that efforts are underway to determine where these drugs might fit in.

Sharon Worcester/Frontline Medical News

Pacritinib

This JAK2/FT3 inhibitor reduces splenomegaly and its related symptoms, but may also help patients who have low platelet counts and a worse prognosis. Pacritinib has demonstrated safety in that population, said Dr. Mesa of Mayo Clinic Cancer Center, Phoenix, Ariz.

Concerns about increased mortality related to risk of intracranial hemorrhage and cardiovascular events led the Food and Drug Administration to place a full clinical hold on pacritinib in February 2016. That hold was lifted in January 2017 when data from the randomized, controlled, phase III PERSIST-2 study, as presented at the American Society of Hematology annual meeting in December 2016, showed the risks did not hold up among study patients.

PERSIST-2 compared pacritinib doses of 400 mg once daily and 200 mg twice daily with best alternative therapy, which was ruxolitinib in most patients, Dr. Mesa said. He noted that the study included patients who had marked thrombocytopenia and were allowed prior JAK2 inhibitor exposure.

The 200-mg twice-daily dosing was superior in achieving spleen volume reductions greater than 35%: 22% of patients in the 200-mg dosing group vs. 15% in the 400-mg once-daily dosing group, compared with 3% of those receiving best available therapy. The twice-daily dosing group also experienced greater symptom improvement: Thirty-two percent in the 200-mg twice-daily group vs. 17% in the 400-mg once-daily group achieved at least a 50% reduction in total symptom scale scores, compared with 14% of those receiving best available therapy.

Additional studies of pacritinib will begin enrolling soon, Dr. Mesa said, noting that these studies will look at lower doses in an effort to identify the minimally effective dose with the optimal balance of safety and efficacy.

Momelotinib

Momelotinib, a JAK1/JAK2 inhibitor, was evaluated in two large recently concluded phase III trials (SIMPLIFY-1 and SIMPLIFY-2). SIMPIFY-1 compared momelotinib to ruxolitinib in the front-line setting, and showed momelotinib to be noninferior for reducing splenomegaly.

“However, it was inferior for improvement in the symptom burden,” Dr. Mesa said, noting that while there seemed to be a favorable difference in terms of anemia, the study was structured in such a way that the agent needed to be noninferior for both spleen and symptoms for the anemia response to be evaluable.

SIMPLIFY-2 evaluated momelotinib in patients who had not responded to ruxolitinib. In this second-line setting, momelotinib was not superior to the best alternative therapy, but since the vast majority of the ruxolitinib failure patients remained on ruxolitinib, it is “a bit of a confounded study to assess,” he said.

The top-line data from these studies were issued in a press release from the manufacturer (Gilead) in November 2016, and the complete results are expected to be made public in the near future, at which time more will be known about the next steps for momelotinib, he said.

If approved, pacritinib and momelotinib could ultimately be positioned as a front-line and/or second-line treatment for myelofibrosis, Dr. Mesa predicted.

There has been a goal, in terms of trial design, to see if there is a niche for these drugs in the front-line setting based on blood counts.

“Those recommendations would clearly be very much dependent on the risk, the safety, and the efficacy,” he said.

PRM-151

This antifibrosing agent was shown to be active in early-phase trials – including in stage 1 of an adaptive phase II trial. PRM-151 is currently being evaluated in the fully-accrued ongoing phase II PROMOTE study to determine whether it improves splenomegaly, symptoms, and cytopenia. The primary endpoint of the study is the bone marrow response rate. Study subjects are patients with primary myelofibrosis, post–polycythemia vera myelofibrosis, or post–essential thrombocythemia myelofibrosis, and grade 2-3 fibrosis, said Dr. Mesa, who is the principal investigator for the study.

Imetelstat

This telomerase inhibitor is being evaluated in the randomized, multicenter, phase II IMbark study, designed to assess spleen volume and total symptom score as primary end points. Earlier studies have shown deep responses in patients with myelofibrosis who were treated with imetelstat, Dr. Mesa said.

The IMbark study (NCT02426086) was originally designed to evaluate two dosing regimens administered as a single agent to participants with intermediate-2 or high-risk myelofibrosis who were refractory to or relapsed after JAK inhibitor treatment. Participants received either 9.4 mg/kg or 4.7 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or study end.

According to information from Geron, which is developing the agent, enrollment of new participants is currently suspended following a planned internal data review, but enrollment “may be resumed after a second internal data review that is planned by the end of the second quarter of 2017.” If resumed, enrollment would be only to the higher-dose treatment arm; patients initially randomized to that arm may continue treatment, and those randomized to the lower-dose arm may see their dose increased at the investigator’s discretion.

If approved, PRM-151 and imetelstat would likely be positioned as second-line treatments for myelofibrosis, Dr. Mesa said, noting that determining which patients would be most likely to benefit from treatment with these agents would require a close look at the evidence from second-line studies.

Combination therapies

In addition to these investigational treatments, nearly 20 different combination treatments involving ruxolitinib plus another agent have been looked at to try to further improve activity. Some improvements in splenomegaly have been seen with combinations including ruxolitinib and either panobinostat (a histone deacytelase inhibitor), LDE225 (a hedgehog signaling pathway inhibitor), and BKM120 (a PI3-kinase inhibitor), he noted.

“For the area of greatest interest – which was to see incremental improvements in thrombocytopenia, anemia, or fibrosis – there have been favorable data, but they have been modest. It’s not quite clear that there is a combination that is ready for prime time, nor is there yet a combination that we have recommended through the treatment guidelines to be utilized for these patients,” he said.

Dr. Mesa has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals; Celgene Corporation, CTI BioPharma, the maker of pacritinib; Galena Biopharma; Gilead, the maker of momelotinib; Incyte, the maker of ruxolitinib; Novartis, the maker of panobinostat and BKM120; and Promedior, the maker of PRM-151.

[email protected]

Jae Park, MD

WASHINGTON, DC—Results of a retrospective study suggest pretreatment disease burden impacts the outcome of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Patients who had minimal residual disease (MRD) prior to treatment had superior event-free and overall survival compared to patients who had morphologic disease before treatment.

Patients with MRD were also less likely to experience cytokine release syndrome (CRS) and neurologic toxicity.

Jae Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, presented these results at the AACR Annual Meeting 2017 (abstract CT078).

This study was funded by Juno Therapeutics, the National Cancer Institute, the Terry Fox Foundation, and MSKCC Experimental Therapeutics Center.

“[W]e and other groups have developed and tested CD19-specific [19-28z] CAR T-cell therapy and have reported encouraging results, with high initial complete response rates in patients with B-ALL,” Dr Park said.

“However, relapses are common, even after achieving seemingly deep remission, and severe toxicities have been observed in some patients.”

To gain more insight into these results, Dr Park and his colleagues retrospectively analyzed data from a prospective clinical trial that tested 19-28z CAR T-cell therapy in patients with B-ALL.

All 51 adults in this trial had relapsed after or were refractory to 1 or more conventional multiagent chemotherapy regimens.

The researchers measured disease burden prior to CAR T-cell infusion in all patients and divided them into 2 cohorts:

• 20 patients who had MRD—less than 5% blasts in the bone marrow
• 31 patients who had morphologic disease—5% or more blasts in the bone marrow.

Response and survival

The complete response rate was 95% in the MRD cohort and 77% in the morphologic disease cohort, a difference that was not statistically significant.

At a median follow-up of 18 months, the median event-free survival and overall survival had not been reached for patients in the MRD cohort (because most were still alive and disease-free).

However, for patients in the morphologic disease cohort, the median event-free survival was 6.3 months (P=0.0005), and the median overall survival was 17 months (P=0.0189).

Role of transplant

The researchers found that long-term survival did not improve for patients who proceeded to hematopoietic stem cell transplant (HSCT), regardless of their disease burden at baseline.

“While more patients and longer follow-up will be needed to adequately address the significance of HSCT, the result of this analysis raises a question as to whether 19-28z CAR therapy can be considered as a definitive, curative therapy rather than a bridge to stem cell transplant, at least in a subset of patients,” Dr Park noted.

“Our data suggest that incorporation of 19-28z CAR T cells at the time of MRD following first-line chemotherapy will maximize the durability of CAR T-cell-mediated remissions and survival and can potentially spare these high-risk patients from HSCT, rather than waiting until they relapse morphologically and then trying CAR T-cell therapy when it is less likely to achieve a durable long-term outcome.”

Adverse events and limitations

Patients from the MRD cohort fared better than the morphologic disease cohort in terms of CRS and neurologic toxicity.

Forty-two percent of patients in the morphologic disease cohort developed CRS, compared to 5% of patients in the MRD cohort (P=0.0326).

Neurologic toxicity occurred in 58% of patients in the morphologic disease cohort and 15% of those in the MRD cohort (P=0.0001).

Dr Park noted that a limitation of this study is its retrospective nature, and the findings will need to be validated prospectively.

Furthermore, the analysis on the impact of allogeneic HSCT was limited by a relatively small sample size in each cohort.

Jae Park, MD

WASHINGTON, DC—Results of a retrospective study suggest pretreatment disease burden impacts the outcome of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Patients who had minimal residual disease (MRD) prior to treatment had superior event-free and overall survival compared to patients who had morphologic disease before treatment.

Patients with MRD were also less likely to experience cytokine release syndrome (CRS) and neurologic toxicity.

Jae Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, presented these results at the AACR Annual Meeting 2017 (abstract CT078).

This study was funded by Juno Therapeutics, the National Cancer Institute, the Terry Fox Foundation, and MSKCC Experimental Therapeutics Center.

“[W]e and other groups have developed and tested CD19-specific [19-28z] CAR T-cell therapy and have reported encouraging results, with high initial complete response rates in patients with B-ALL,” Dr Park said.

“However, relapses are common, even after achieving seemingly deep remission, and severe toxicities have been observed in some patients.”

To gain more insight into these results, Dr Park and his colleagues retrospectively analyzed data from a prospective clinical trial that tested 19-28z CAR T-cell therapy in patients with B-ALL.

All 51 adults in this trial had relapsed after or were refractory to 1 or more conventional multiagent chemotherapy regimens.

The researchers measured disease burden prior to CAR T-cell infusion in all patients and divided them into 2 cohorts:

• 20 patients who had MRD—less than 5% blasts in the bone marrow
• 31 patients who had morphologic disease—5% or more blasts in the bone marrow.

Response and survival

The complete response rate was 95% in the MRD cohort and 77% in the morphologic disease cohort, a difference that was not statistically significant.

At a median follow-up of 18 months, the median event-free survival and overall survival had not been reached for patients in the MRD cohort (because most were still alive and disease-free).

However, for patients in the morphologic disease cohort, the median event-free survival was 6.3 months (P=0.0005), and the median overall survival was 17 months (P=0.0189).

Role of transplant

The researchers found that long-term survival did not improve for patients who proceeded to hematopoietic stem cell transplant (HSCT), regardless of their disease burden at baseline.

“While more patients and longer follow-up will be needed to adequately address the significance of HSCT, the result of this analysis raises a question as to whether 19-28z CAR therapy can be considered as a definitive, curative therapy rather than a bridge to stem cell transplant, at least in a subset of patients,” Dr Park noted.

“Our data suggest that incorporation of 19-28z CAR T cells at the time of MRD following first-line chemotherapy will maximize the durability of CAR T-cell-mediated remissions and survival and can potentially spare these high-risk patients from HSCT, rather than waiting until they relapse morphologically and then trying CAR T-cell therapy when it is less likely to achieve a durable long-term outcome.”

Adverse events and limitations

Patients from the MRD cohort fared better than the morphologic disease cohort in terms of CRS and neurologic toxicity.

Forty-two percent of patients in the morphologic disease cohort developed CRS, compared to 5% of patients in the MRD cohort (P=0.0326).

Neurologic toxicity occurred in 58% of patients in the morphologic disease cohort and 15% of those in the MRD cohort (P=0.0001).

Dr Park noted that a limitation of this study is its retrospective nature, and the findings will need to be validated prospectively.

Furthermore, the analysis on the impact of allogeneic HSCT was limited by a relatively small sample size in each cohort.

Jae Park, MD

WASHINGTON, DC—Results of a retrospective study suggest pretreatment disease burden impacts the outcome of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).

Patients who had minimal residual disease (MRD) prior to treatment had superior event-free and overall survival compared to patients who had morphologic disease before treatment.

Patients with MRD were also less likely to experience cytokine release syndrome (CRS) and neurologic toxicity.

Jae Park, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, New York, presented these results at the AACR Annual Meeting 2017 (abstract CT078).

This study was funded by Juno Therapeutics, the National Cancer Institute, the Terry Fox Foundation, and MSKCC Experimental Therapeutics Center.

“[W]e and other groups have developed and tested CD19-specific [19-28z] CAR T-cell therapy and have reported encouraging results, with high initial complete response rates in patients with B-ALL,” Dr Park said.

“However, relapses are common, even after achieving seemingly deep remission, and severe toxicities have been observed in some patients.”

To gain more insight into these results, Dr Park and his colleagues retrospectively analyzed data from a prospective clinical trial that tested 19-28z CAR T-cell therapy in patients with B-ALL.

All 51 adults in this trial had relapsed after or were refractory to 1 or more conventional multiagent chemotherapy regimens.

The researchers measured disease burden prior to CAR T-cell infusion in all patients and divided them into 2 cohorts:

• 20 patients who had MRD—less than 5% blasts in the bone marrow
• 31 patients who had morphologic disease—5% or more blasts in the bone marrow.

Response and survival

The complete response rate was 95% in the MRD cohort and 77% in the morphologic disease cohort, a difference that was not statistically significant.

At a median follow-up of 18 months, the median event-free survival and overall survival had not been reached for patients in the MRD cohort (because most were still alive and disease-free).

However, for patients in the morphologic disease cohort, the median event-free survival was 6.3 months (P=0.0005), and the median overall survival was 17 months (P=0.0189).

Role of transplant

The researchers found that long-term survival did not improve for patients who proceeded to hematopoietic stem cell transplant (HSCT), regardless of their disease burden at baseline.

“While more patients and longer follow-up will be needed to adequately address the significance of HSCT, the result of this analysis raises a question as to whether 19-28z CAR therapy can be considered as a definitive, curative therapy rather than a bridge to stem cell transplant, at least in a subset of patients,” Dr Park noted.

“Our data suggest that incorporation of 19-28z CAR T cells at the time of MRD following first-line chemotherapy will maximize the durability of CAR T-cell-mediated remissions and survival and can potentially spare these high-risk patients from HSCT, rather than waiting until they relapse morphologically and then trying CAR T-cell therapy when it is less likely to achieve a durable long-term outcome.”

Adverse events and limitations

Patients from the MRD cohort fared better than the morphologic disease cohort in terms of CRS and neurologic toxicity.

Forty-two percent of patients in the morphologic disease cohort developed CRS, compared to 5% of patients in the MRD cohort (P=0.0326).

Neurologic toxicity occurred in 58% of patients in the morphologic disease cohort and 15% of those in the MRD cohort (P=0.0001).

Dr Park noted that a limitation of this study is its retrospective nature, and the findings will need to be validated prospectively.

Furthermore, the analysis on the impact of allogeneic HSCT was limited by a relatively small sample size in each cohort.

Image by Claus Azzalin

WASHINGTON, DC—Telomere length may predict cancer risk and could be a target for future therapies, according to research presented at the AACR Annual Meeting 2017.

The study suggests that, overall, longer-than-expected telomeres are associated with an increased risk of cancer.

However, investigators also found an increased risk of certain cancers, including leukemia, among patients who had very short or very long telomeres.

“Telomeres and cancer clearly have a complex relationship,” said study investigator Jian-Min Yuan, MD, PhD, of the University of Pittsburgh Cancer Institute in Pennsylvania.

“Our hope is that by understanding this relationship, we may be able to predict which people are most likely to develop certain cancers so they can take preventive measures and perhaps be screened more often, as well as develop therapies to help our DNA keep or return its telomeres to a healthy length.”

Dr Yuan and his colleagues presented their research as abstract 2267/21.*

The team analyzed blood samples and health data on 26,540 individuals enrolled in the Singapore Chinese Health Study, which has followed the health outcomes of participants since 1993. As of the end of 2015, 4060 participants had developed cancer (77 with leukemia).

The investigators divided participants into 5 groups, based on the length of their telomeres.

The group with the longest telomeres (quartile 5) had a significantly higher risk of developing any cancer than the group with the shortest telomeres (quartile 1), after taking into account the effects of age, sex, education, body mass index, smoking habits, and alcohol consumption. The hazard ratio (HR) was 1.33 (P<0.0001).

In particular, the group with the longest telomeres had a significantly increased risk of colorectal cancer (HR=1.37, P=0.010), breast cancer (HR=1.39, P=0.007), prostate cancer (HR=1.55, P=0.011), and pancreatic cancer (HR=2.58, P=0.009).

On the other hand, the risk of liver cancer decreased as telomere length increased. The HR was 0.72 for patients in quartile 5 compared to those in quartile 1 (P_linear=0.056).

The risk of 3 cancers was greatest for both the groups with extremely short and extremely long telomeres­—quartiles 1 and 5, respectively.

For leukemia, the HR was 2.15 for quartile 1 and 1.68 for quartile 5, when compared to quartile 3 (P_non-linear=0.015).

For bladder cancer, the HRs were 1.72 and 2.17, respectively (P_non-linear=0.01). And for stomach cancer, the HRs were 1.63 and 1.55, respectively (P_non-linear=0.020).

“We had the idea for this study more than 7 years ago, but it took the laboratory 3 months to finish quantifying telomere length for just 100 samples, which was not enough to draw any meaningful conclusions,” Dr Yuan said.

“Not even a decade later, we’ve been able to run nearly 30,000 samples in a year and draw these really robust insights, showing how far technology has come. Even more complicated will be linking telomere length to genome-wide analyses, which is on the horizon. We’re on the cusp of gaining a truly remarkable understanding of the complicated biological phenomena that lead to cancer.”

*The presentation differed from the abstract.

Image by Claus Azzalin

WASHINGTON, DC—Telomere length may predict cancer risk and could be a target for future therapies, according to research presented at the AACR Annual Meeting 2017.

The study suggests that, overall, longer-than-expected telomeres are associated with an increased risk of cancer.

However, investigators also found an increased risk of certain cancers, including leukemia, among patients who had very short or very long telomeres.

“Telomeres and cancer clearly have a complex relationship,” said study investigator Jian-Min Yuan, MD, PhD, of the University of Pittsburgh Cancer Institute in Pennsylvania.

“Our hope is that by understanding this relationship, we may be able to predict which people are most likely to develop certain cancers so they can take preventive measures and perhaps be screened more often, as well as develop therapies to help our DNA keep or return its telomeres to a healthy length.”

Dr Yuan and his colleagues presented their research as abstract 2267/21.*

The team analyzed blood samples and health data on 26,540 individuals enrolled in the Singapore Chinese Health Study, which has followed the health outcomes of participants since 1993. As of the end of 2015, 4060 participants had developed cancer (77 with leukemia).

The investigators divided participants into 5 groups, based on the length of their telomeres.

The group with the longest telomeres (quartile 5) had a significantly higher risk of developing any cancer than the group with the shortest telomeres (quartile 1), after taking into account the effects of age, sex, education, body mass index, smoking habits, and alcohol consumption. The hazard ratio (HR) was 1.33 (P<0.0001).

In particular, the group with the longest telomeres had a significantly increased risk of colorectal cancer (HR=1.37, P=0.010), breast cancer (HR=1.39, P=0.007), prostate cancer (HR=1.55, P=0.011), and pancreatic cancer (HR=2.58, P=0.009).

On the other hand, the risk of liver cancer decreased as telomere length increased. The HR was 0.72 for patients in quartile 5 compared to those in quartile 1 (P_linear=0.056).

The risk of 3 cancers was greatest for both the groups with extremely short and extremely long telomeres­—quartiles 1 and 5, respectively.

For leukemia, the HR was 2.15 for quartile 1 and 1.68 for quartile 5, when compared to quartile 3 (P_non-linear=0.015).

For bladder cancer, the HRs were 1.72 and 2.17, respectively (P_non-linear=0.01). And for stomach cancer, the HRs were 1.63 and 1.55, respectively (P_non-linear=0.020).

“We had the idea for this study more than 7 years ago, but it took the laboratory 3 months to finish quantifying telomere length for just 100 samples, which was not enough to draw any meaningful conclusions,” Dr Yuan said.

“Not even a decade later, we’ve been able to run nearly 30,000 samples in a year and draw these really robust insights, showing how far technology has come. Even more complicated will be linking telomere length to genome-wide analyses, which is on the horizon. We’re on the cusp of gaining a truly remarkable understanding of the complicated biological phenomena that lead to cancer.”

*The presentation differed from the abstract.

Image by Claus Azzalin

WASHINGTON, DC—Telomere length may predict cancer risk and could be a target for future therapies, according to research presented at the AACR Annual Meeting 2017.

The study suggests that, overall, longer-than-expected telomeres are associated with an increased risk of cancer.

However, investigators also found an increased risk of certain cancers, including leukemia, among patients who had very short or very long telomeres.

“Telomeres and cancer clearly have a complex relationship,” said study investigator Jian-Min Yuan, MD, PhD, of the University of Pittsburgh Cancer Institute in Pennsylvania.

“Our hope is that by understanding this relationship, we may be able to predict which people are most likely to develop certain cancers so they can take preventive measures and perhaps be screened more often, as well as develop therapies to help our DNA keep or return its telomeres to a healthy length.”

Dr Yuan and his colleagues presented their research as abstract 2267/21.*

The team analyzed blood samples and health data on 26,540 individuals enrolled in the Singapore Chinese Health Study, which has followed the health outcomes of participants since 1993. As of the end of 2015, 4060 participants had developed cancer (77 with leukemia).

The investigators divided participants into 5 groups, based on the length of their telomeres.

The group with the longest telomeres (quartile 5) had a significantly higher risk of developing any cancer than the group with the shortest telomeres (quartile 1), after taking into account the effects of age, sex, education, body mass index, smoking habits, and alcohol consumption. The hazard ratio (HR) was 1.33 (P<0.0001).

In particular, the group with the longest telomeres had a significantly increased risk of colorectal cancer (HR=1.37, P=0.010), breast cancer (HR=1.39, P=0.007), prostate cancer (HR=1.55, P=0.011), and pancreatic cancer (HR=2.58, P=0.009).

On the other hand, the risk of liver cancer decreased as telomere length increased. The HR was 0.72 for patients in quartile 5 compared to those in quartile 1 (P_linear=0.056).

The risk of 3 cancers was greatest for both the groups with extremely short and extremely long telomeres­—quartiles 1 and 5, respectively.

For leukemia, the HR was 2.15 for quartile 1 and 1.68 for quartile 5, when compared to quartile 3 (P_non-linear=0.015).

For bladder cancer, the HRs were 1.72 and 2.17, respectively (P_non-linear=0.01). And for stomach cancer, the HRs were 1.63 and 1.55, respectively (P_non-linear=0.020).

“We had the idea for this study more than 7 years ago, but it took the laboratory 3 months to finish quantifying telomere length for just 100 samples, which was not enough to draw any meaningful conclusions,” Dr Yuan said.

“Not even a decade later, we’ve been able to run nearly 30,000 samples in a year and draw these really robust insights, showing how far technology has come. Even more complicated will be linking telomere length to genome-wide analyses, which is on the horizon. We’re on the cusp of gaining a truly remarkable understanding of the complicated biological phenomena that lead to cancer.”

*The presentation differed from the abstract.

ORLANDO – Referral to a specialized center with expertise in the management of myeloproliferative neoplasms is strongly recommended for all patients diagnosed with myelofibrosis, according to a new treatment guideline from the National Comprehensive Cancer Network.

The guideline is the first in a series addressing myeloproliferative neoplasms (MPNs), and it focuses on the diagnostic work-up of MPNs, as well as the treatment of myelofibrosis. The guideline panel, led by panel chair Ruben A. Mesa, MD, is working next on guidelines for the other two “core classic” Philadelphia chromosome–negative MPNs: polycythemia vera, and essential thrombocythemia.

Sharon Worcester/Frontline Medical News

COMFORT-1 update: ruxolitinib responses durable in myelofibrosis

To date, ruxolitinib is the only Food and Drug Administration–approved drug for the treatment of myelofibrosis.

The randomized controlled phase III COMFORT I and II trials conducted in the United States and Europe, respectively, demonstrated that the oral JAK1/JAK2 inhibitor has a rapid, beneficial impact on both survival and disease-associated enlargement of the spleen and improvement in related symptoms, Dr. Mesa said.

A 5-year update on data from 309 patients in the COMFORT-1 trial, as reported at the annual meeting of the American Society of Clinical Oncology in 2016, confirmed the durability of treatment responses to ruxolitinib in patients initially randomized to receive the drug, he said.

“We were able to demonstrate a continued survival advantage for those individuals receiving ruxolitinib,” he added.

At weeks 24 and 264, the mean spleen volume reduction was 31.6% and 37.6%, respectively, in those originally randomized to ruxolitinib. The median duration of at least 35% spleen volume reduction was 168.3 weeks.

Overall survival favored ruxolitinib (hazard ratio, 0.69). Median overall survival in the ruxolitinib group had not yet been reached.

“But we realize our work is not done. The survival curve does not plateau; we are not curing these patients. We’re having meaningful impact, but we have room to continue to improve,” he said.

Also, there is an initial drop in platelet counts that tends to stabilize, but not improve, and there is worsening of anemia (new onset grade 3 or 4 anemia was 25.2% with ruxolitinib, and 26.1% in 111 of 154 patients who crossed over from the placebo group), and although this tends to improve, these are among areas of unmet need, he added.

Further, long-term risks of treatment include cutaneous malignancies (basal cell carcinoma occurred in 7.7% and 9.0% of treatment and crossover patients, respectively), which are difficult to separate from baseline hydroxyurea use, and increased risk of herpes zoster (which occurred in 10.3% and 13.5% of treated and crossover patients).

However, there appears to be no increased risk – and there may be a slight decreased risk – of progression to acute leukemia, Dr. Mesa said.

Dr. Mesa disclosed that he has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals, Celgene, CTI BioPharma, Galena Biopharma, Gilead Sciences, Incyte, Novartis Pharmaceuticals, and Promedior.

[email protected]

ORLANDO – Referral to a specialized center with expertise in the management of myeloproliferative neoplasms is strongly recommended for all patients diagnosed with myelofibrosis, according to a new treatment guideline from the National Comprehensive Cancer Network.

The guideline is the first in a series addressing myeloproliferative neoplasms (MPNs), and it focuses on the diagnostic work-up of MPNs, as well as the treatment of myelofibrosis. The guideline panel, led by panel chair Ruben A. Mesa, MD, is working next on guidelines for the other two “core classic” Philadelphia chromosome–negative MPNs: polycythemia vera, and essential thrombocythemia.

Sharon Worcester/Frontline Medical News

COMFORT-1 update: ruxolitinib responses durable in myelofibrosis

To date, ruxolitinib is the only Food and Drug Administration–approved drug for the treatment of myelofibrosis.

The randomized controlled phase III COMFORT I and II trials conducted in the United States and Europe, respectively, demonstrated that the oral JAK1/JAK2 inhibitor has a rapid, beneficial impact on both survival and disease-associated enlargement of the spleen and improvement in related symptoms, Dr. Mesa said.

A 5-year update on data from 309 patients in the COMFORT-1 trial, as reported at the annual meeting of the American Society of Clinical Oncology in 2016, confirmed the durability of treatment responses to ruxolitinib in patients initially randomized to receive the drug, he said.

“We were able to demonstrate a continued survival advantage for those individuals receiving ruxolitinib,” he added.

At weeks 24 and 264, the mean spleen volume reduction was 31.6% and 37.6%, respectively, in those originally randomized to ruxolitinib. The median duration of at least 35% spleen volume reduction was 168.3 weeks.

Overall survival favored ruxolitinib (hazard ratio, 0.69). Median overall survival in the ruxolitinib group had not yet been reached.

“But we realize our work is not done. The survival curve does not plateau; we are not curing these patients. We’re having meaningful impact, but we have room to continue to improve,” he said.

Also, there is an initial drop in platelet counts that tends to stabilize, but not improve, and there is worsening of anemia (new onset grade 3 or 4 anemia was 25.2% with ruxolitinib, and 26.1% in 111 of 154 patients who crossed over from the placebo group), and although this tends to improve, these are among areas of unmet need, he added.

Further, long-term risks of treatment include cutaneous malignancies (basal cell carcinoma occurred in 7.7% and 9.0% of treatment and crossover patients, respectively), which are difficult to separate from baseline hydroxyurea use, and increased risk of herpes zoster (which occurred in 10.3% and 13.5% of treated and crossover patients).

However, there appears to be no increased risk – and there may be a slight decreased risk – of progression to acute leukemia, Dr. Mesa said.

Dr. Mesa disclosed that he has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals, Celgene, CTI BioPharma, Galena Biopharma, Gilead Sciences, Incyte, Novartis Pharmaceuticals, and Promedior.

[email protected]

ORLANDO – Referral to a specialized center with expertise in the management of myeloproliferative neoplasms is strongly recommended for all patients diagnosed with myelofibrosis, according to a new treatment guideline from the National Comprehensive Cancer Network.

The guideline is the first in a series addressing myeloproliferative neoplasms (MPNs), and it focuses on the diagnostic work-up of MPNs, as well as the treatment of myelofibrosis. The guideline panel, led by panel chair Ruben A. Mesa, MD, is working next on guidelines for the other two “core classic” Philadelphia chromosome–negative MPNs: polycythemia vera, and essential thrombocythemia.

Sharon Worcester/Frontline Medical News

COMFORT-1 update: ruxolitinib responses durable in myelofibrosis

To date, ruxolitinib is the only Food and Drug Administration–approved drug for the treatment of myelofibrosis.

The randomized controlled phase III COMFORT I and II trials conducted in the United States and Europe, respectively, demonstrated that the oral JAK1/JAK2 inhibitor has a rapid, beneficial impact on both survival and disease-associated enlargement of the spleen and improvement in related symptoms, Dr. Mesa said.

A 5-year update on data from 309 patients in the COMFORT-1 trial, as reported at the annual meeting of the American Society of Clinical Oncology in 2016, confirmed the durability of treatment responses to ruxolitinib in patients initially randomized to receive the drug, he said.

“We were able to demonstrate a continued survival advantage for those individuals receiving ruxolitinib,” he added.

At weeks 24 and 264, the mean spleen volume reduction was 31.6% and 37.6%, respectively, in those originally randomized to ruxolitinib. The median duration of at least 35% spleen volume reduction was 168.3 weeks.

Overall survival favored ruxolitinib (hazard ratio, 0.69). Median overall survival in the ruxolitinib group had not yet been reached.

“But we realize our work is not done. The survival curve does not plateau; we are not curing these patients. We’re having meaningful impact, but we have room to continue to improve,” he said.

Also, there is an initial drop in platelet counts that tends to stabilize, but not improve, and there is worsening of anemia (new onset grade 3 or 4 anemia was 25.2% with ruxolitinib, and 26.1% in 111 of 154 patients who crossed over from the placebo group), and although this tends to improve, these are among areas of unmet need, he added.

Further, long-term risks of treatment include cutaneous malignancies (basal cell carcinoma occurred in 7.7% and 9.0% of treatment and crossover patients, respectively), which are difficult to separate from baseline hydroxyurea use, and increased risk of herpes zoster (which occurred in 10.3% and 13.5% of treated and crossover patients).

However, there appears to be no increased risk – and there may be a slight decreased risk – of progression to acute leukemia, Dr. Mesa said.

Dr. Mesa disclosed that he has received consulting fees, honoraria, and/or grant/research support from ARIAD Pharmaceuticals, Celgene, CTI BioPharma, Galena Biopharma, Gilead Sciences, Incyte, Novartis Pharmaceuticals, and Promedior.

[email protected]

ORLANDO – Infusions of banked multivirus-specific T lymphocytes were associated with complete or partial responses in 93% of 42 patients who had undergone hematopoietic cell transplants and had drug-refractory viral illnesses. Further, these patients experienced minimal new or reactivated graft-versus-host disease (GVHD).

Viral infections cause nearly 40% of deaths after alternative donor hematopoietic cell transfer (HCT), Ifigeneia Tzannou, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation. Banked, “off-the-shelf” donor virus-resistant T cells can be an alternative to antiviral drugs, which are far from universally effective and may have serious side effects.

Kari Oakes/Frontline Medical News

[email protected]

On Twitter @karioakes

ORLANDO – Infusions of banked multivirus-specific T lymphocytes were associated with complete or partial responses in 93% of 42 patients who had undergone hematopoietic cell transplants and had drug-refractory viral illnesses. Further, these patients experienced minimal new or reactivated graft-versus-host disease (GVHD).

Viral infections cause nearly 40% of deaths after alternative donor hematopoietic cell transfer (HCT), Ifigeneia Tzannou, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation. Banked, “off-the-shelf” donor virus-resistant T cells can be an alternative to antiviral drugs, which are far from universally effective and may have serious side effects.

Kari Oakes/Frontline Medical News

[email protected]

On Twitter @karioakes

ORLANDO – Infusions of banked multivirus-specific T lymphocytes were associated with complete or partial responses in 93% of 42 patients who had undergone hematopoietic cell transplants and had drug-refractory viral illnesses. Further, these patients experienced minimal new or reactivated graft-versus-host disease (GVHD).

Viral infections cause nearly 40% of deaths after alternative donor hematopoietic cell transfer (HCT), Ifigeneia Tzannou, MD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation. Banked, “off-the-shelf” donor virus-resistant T cells can be an alternative to antiviral drugs, which are far from universally effective and may have serious side effects.

Kari Oakes/Frontline Medical News

[email protected]

On Twitter @karioakes

ORLANDO – Tocilizumab plus standard immune suppression appears to drive down the risk for graft-versus-host disease (GVHD), according to results from a phase II study of 35 adults undergoing allogeneic stem cell transplants.

The effect was particularly pronounced for prevention of GVHD in the colon, William Drobyski, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The incidence rate of grades II-IV and III-IV acute GVHD was 12% at day 100 in patients given standard prophylaxis of tacrolimus/methotrexate (Tac/MTX) and 3% in patients given Tac/MTX plus 8 mg/kg of tocilizumab (Toc, capped at 800 mg), said Dr. Drobyski of the Medical College of Wisconsin, Milwaukee.

To provide further context to the results, Dr. Drobyski and his colleagues performed a matched case-control analysis using contemporary controls in the Center for International Blood & Marrow Transplant Research from 2000 to 2014. The same eligibility criteria used for the trial were applied to the matched controls except for the use of Tac/MTX as GVHD prophylaxis. Patients were otherwise matched based on age, performance score, disease, and donor type.

The incidence of grades II-IV acute GVHD at day 100 was significantly lower in the Toc/Tac/MTX group than in the Tac/MTX control population (12% vs. 41%). The incidence of grades III-IV acute GVHD was slightly lower with tocilizumab, but the difference between the groups was not statistically significant, Dr. Drobyski said.

The probability of grade II-IV acute GVHD–free survival, which was the primary endpoint of the study, was significantly higher in the Toc/Tac/MTX group (79% vs 52%), he said.

Five patients developed grade 2 acute GVHD of the skin or upper GI tract, and one patient died of grade 4 acute GVHD of the skin in the first 100 days. Notably, there were no cases of acute GVHD of the lower GI tract during that time, although two cases did occur between days 130 and 180, he said.

“There was no difference in transplant-related mortality, relapse, disease-free survival, or overall survival,” he said, adding that preliminary data suggest there were no differences in chronic GVHD between the groups.

Causes of death also were similar between the two cohorts with respect to disease- and transplant-related complications.

Patients in the tocilizumab study were enrolled between January 2015 and June 2016; the median age was 66 years. Diseases represented in the cohort included de novo acute myeloid leukemia (13 patients), AML (6 patients), chronic myelomonocytic leukemia (6 patients), acute lymphoblastic leukemia (4 patients), myelodysplastic syndrome (3 patients), and T-cell lymphoma, chronic myeloid leukemia, and NK/T cell lymphoma (in 1 patient each). Most patients were classified as high risk (9 patients) or intermediate risk (22 patients) by the disease risk index.

Conditioning was entirely busulfan based. Myeloablative conditioning was with busulfan and cyclophosphamide (Cytoxan) in 5 patients, or fludarabine and 4 days of busulfan in 10 patients, and reduced-intensity conditioning was with fludarabine and 2 days of busulfan in 18 patients. Transplants were with either HLA-matched related or unrelated donor grafts. Most patients (29 of 35) received peripheral stem cell grafts.

Tocilizumab, an interleuken-6 receptor blocker that is approved for treatment of rheumatoid arthritis, was administered after completion of conditioning and on the day prior to stem cell infusion.

In a pilot clinical trial of tocilizumab for the treatment of steroid-resistant acute GVHD in patients who had primarily had lower GI tract disease, “we were able to demonstrate responses in a majority of these patients,” Dr. Drobyski said, noting that a recent study presented at the 2016 annual meeting of the American Society of Hematology also showed efficacy in the treatment of lower tract GI GVHD, “providing evidence that tocilizumab had activity in acute GVHD, and perhaps in the treatment of steroid-refractory lower GI GVHD.”

Elevated IL-6 levels in the peripheral blood are correlated with an increased incidence and severity of GVHD; administration of an anti-IL-6 receptor antibody has been shown in preclinical studies to protect mice from lethal GVHD. The current open-label study was performed to “try to advance this concept” by assessing whether inhibition of IL-6 signaling could also prevent acute GVHD.

The findings confirm those of a 2014 study by Kennedy et al. in Lancet Oncology (2014;15:1451-9), and imply that tocilizumab warrants a randomized trial as prophylaxis for acute GVHD, he concluded.

Dr. Drobyski reported having no disclosures.

[email protected]

ORLANDO – Tocilizumab plus standard immune suppression appears to drive down the risk for graft-versus-host disease (GVHD), according to results from a phase II study of 35 adults undergoing allogeneic stem cell transplants.

The effect was particularly pronounced for prevention of GVHD in the colon, William Drobyski, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The incidence rate of grades II-IV and III-IV acute GVHD was 12% at day 100 in patients given standard prophylaxis of tacrolimus/methotrexate (Tac/MTX) and 3% in patients given Tac/MTX plus 8 mg/kg of tocilizumab (Toc, capped at 800 mg), said Dr. Drobyski of the Medical College of Wisconsin, Milwaukee.

To provide further context to the results, Dr. Drobyski and his colleagues performed a matched case-control analysis using contemporary controls in the Center for International Blood & Marrow Transplant Research from 2000 to 2014. The same eligibility criteria used for the trial were applied to the matched controls except for the use of Tac/MTX as GVHD prophylaxis. Patients were otherwise matched based on age, performance score, disease, and donor type.

The incidence of grades II-IV acute GVHD at day 100 was significantly lower in the Toc/Tac/MTX group than in the Tac/MTX control population (12% vs. 41%). The incidence of grades III-IV acute GVHD was slightly lower with tocilizumab, but the difference between the groups was not statistically significant, Dr. Drobyski said.

The probability of grade II-IV acute GVHD–free survival, which was the primary endpoint of the study, was significantly higher in the Toc/Tac/MTX group (79% vs 52%), he said.

Five patients developed grade 2 acute GVHD of the skin or upper GI tract, and one patient died of grade 4 acute GVHD of the skin in the first 100 days. Notably, there were no cases of acute GVHD of the lower GI tract during that time, although two cases did occur between days 130 and 180, he said.

“There was no difference in transplant-related mortality, relapse, disease-free survival, or overall survival,” he said, adding that preliminary data suggest there were no differences in chronic GVHD between the groups.

Causes of death also were similar between the two cohorts with respect to disease- and transplant-related complications.

Patients in the tocilizumab study were enrolled between January 2015 and June 2016; the median age was 66 years. Diseases represented in the cohort included de novo acute myeloid leukemia (13 patients), AML (6 patients), chronic myelomonocytic leukemia (6 patients), acute lymphoblastic leukemia (4 patients), myelodysplastic syndrome (3 patients), and T-cell lymphoma, chronic myeloid leukemia, and NK/T cell lymphoma (in 1 patient each). Most patients were classified as high risk (9 patients) or intermediate risk (22 patients) by the disease risk index.

Conditioning was entirely busulfan based. Myeloablative conditioning was with busulfan and cyclophosphamide (Cytoxan) in 5 patients, or fludarabine and 4 days of busulfan in 10 patients, and reduced-intensity conditioning was with fludarabine and 2 days of busulfan in 18 patients. Transplants were with either HLA-matched related or unrelated donor grafts. Most patients (29 of 35) received peripheral stem cell grafts.

Tocilizumab, an interleuken-6 receptor blocker that is approved for treatment of rheumatoid arthritis, was administered after completion of conditioning and on the day prior to stem cell infusion.

In a pilot clinical trial of tocilizumab for the treatment of steroid-resistant acute GVHD in patients who had primarily had lower GI tract disease, “we were able to demonstrate responses in a majority of these patients,” Dr. Drobyski said, noting that a recent study presented at the 2016 annual meeting of the American Society of Hematology also showed efficacy in the treatment of lower tract GI GVHD, “providing evidence that tocilizumab had activity in acute GVHD, and perhaps in the treatment of steroid-refractory lower GI GVHD.”

Elevated IL-6 levels in the peripheral blood are correlated with an increased incidence and severity of GVHD; administration of an anti-IL-6 receptor antibody has been shown in preclinical studies to protect mice from lethal GVHD. The current open-label study was performed to “try to advance this concept” by assessing whether inhibition of IL-6 signaling could also prevent acute GVHD.

The findings confirm those of a 2014 study by Kennedy et al. in Lancet Oncology (2014;15:1451-9), and imply that tocilizumab warrants a randomized trial as prophylaxis for acute GVHD, he concluded.

Dr. Drobyski reported having no disclosures.

[email protected]

ORLANDO – Tocilizumab plus standard immune suppression appears to drive down the risk for graft-versus-host disease (GVHD), according to results from a phase II study of 35 adults undergoing allogeneic stem cell transplants.

The effect was particularly pronounced for prevention of GVHD in the colon, William Drobyski, MD, reported at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.

The incidence rate of grades II-IV and III-IV acute GVHD was 12% at day 100 in patients given standard prophylaxis of tacrolimus/methotrexate (Tac/MTX) and 3% in patients given Tac/MTX plus 8 mg/kg of tocilizumab (Toc, capped at 800 mg), said Dr. Drobyski of the Medical College of Wisconsin, Milwaukee.

To provide further context to the results, Dr. Drobyski and his colleagues performed a matched case-control analysis using contemporary controls in the Center for International Blood & Marrow Transplant Research from 2000 to 2014. The same eligibility criteria used for the trial were applied to the matched controls except for the use of Tac/MTX as GVHD prophylaxis. Patients were otherwise matched based on age, performance score, disease, and donor type.

The incidence of grades II-IV acute GVHD at day 100 was significantly lower in the Toc/Tac/MTX group than in the Tac/MTX control population (12% vs. 41%). The incidence of grades III-IV acute GVHD was slightly lower with tocilizumab, but the difference between the groups was not statistically significant, Dr. Drobyski said.

The probability of grade II-IV acute GVHD–free survival, which was the primary endpoint of the study, was significantly higher in the Toc/Tac/MTX group (79% vs 52%), he said.

Five patients developed grade 2 acute GVHD of the skin or upper GI tract, and one patient died of grade 4 acute GVHD of the skin in the first 100 days. Notably, there were no cases of acute GVHD of the lower GI tract during that time, although two cases did occur between days 130 and 180, he said.

“There was no difference in transplant-related mortality, relapse, disease-free survival, or overall survival,” he said, adding that preliminary data suggest there were no differences in chronic GVHD between the groups.

Causes of death also were similar between the two cohorts with respect to disease- and transplant-related complications.

Patients in the tocilizumab study were enrolled between January 2015 and June 2016; the median age was 66 years. Diseases represented in the cohort included de novo acute myeloid leukemia (13 patients), AML (6 patients), chronic myelomonocytic leukemia (6 patients), acute lymphoblastic leukemia (4 patients), myelodysplastic syndrome (3 patients), and T-cell lymphoma, chronic myeloid leukemia, and NK/T cell lymphoma (in 1 patient each). Most patients were classified as high risk (9 patients) or intermediate risk (22 patients) by the disease risk index.

Conditioning was entirely busulfan based. Myeloablative conditioning was with busulfan and cyclophosphamide (Cytoxan) in 5 patients, or fludarabine and 4 days of busulfan in 10 patients, and reduced-intensity conditioning was with fludarabine and 2 days of busulfan in 18 patients. Transplants were with either HLA-matched related or unrelated donor grafts. Most patients (29 of 35) received peripheral stem cell grafts.

Tocilizumab, an interleuken-6 receptor blocker that is approved for treatment of rheumatoid arthritis, was administered after completion of conditioning and on the day prior to stem cell infusion.

In a pilot clinical trial of tocilizumab for the treatment of steroid-resistant acute GVHD in patients who had primarily had lower GI tract disease, “we were able to demonstrate responses in a majority of these patients,” Dr. Drobyski said, noting that a recent study presented at the 2016 annual meeting of the American Society of Hematology also showed efficacy in the treatment of lower tract GI GVHD, “providing evidence that tocilizumab had activity in acute GVHD, and perhaps in the treatment of steroid-refractory lower GI GVHD.”

Elevated IL-6 levels in the peripheral blood are correlated with an increased incidence and severity of GVHD; administration of an anti-IL-6 receptor antibody has been shown in preclinical studies to protect mice from lethal GVHD. The current open-label study was performed to “try to advance this concept” by assessing whether inhibition of IL-6 signaling could also prevent acute GVHD.

The findings confirm those of a 2014 study by Kennedy et al. in Lancet Oncology (2014;15:1451-9), and imply that tocilizumab warrants a randomized trial as prophylaxis for acute GVHD, he concluded.

Dr. Drobyski reported having no disclosures.

[email protected]

Micrograph showing CLL

WASHINGTON, DC—Preclinical research suggests a second-generation BTK inhibitor may overcome the acquired resistance observed with its predecessor in patients with chronic lymphocytic leukemia (CLL).

Investigators found the non-covalent BTK inhibitor SNS-062 was unaffected by the BTK C481S mutation, which confers resistance to the first-generation BTK inhibitor ibrutinib.

“[A] subset of patients acquire resistance to ibrutinib, the current standard-of-care BTK inhibitor,” said Amy Johnson, PhD, of The Ohio State University in Columbus.

“A key resistance mechanism to covalent BTK inhibitors is a point mutation in the BTK active site, converting cysteine 481 to serine, or C481S.”

“In this study, we demonstrate that SNS-062, which binds non-covalently to BTK, is a potent inhibitor of BTK unaffected by the presence of the C481S mutation. These findings support clinical investigation of SNS-062 to address acquired resistance to covalent BTK inhibitors in patients.”

Dr Johnson and her colleagues presented these findings at the AACR Annual Meeting 2017 (abstract 1207).

SNS-062 is being developed by Sunesis Pharmaceuticals, Inc., and company investigators were involved in this research. But the study was sponsored by The Ohio State University.

For this study, Dr Johnson and her colleagues tested SNS-062 in primary CLL cells and X-linked agammaglobulinemia human cell lines.

The investigators found that SNS-062 inhibited BTK, decreased the expression of B-cell activation markers, and reduced CLL cell viability in a dose-dependent manner. And these effects were comparable to those observed with ibrutinib.

SNS-062 and ibrutinib demonstrated comparable activity against wild-type BTK. However, ibrutinib and another BTK inhibitor, acalabrutinib, were hindered by the BTK C481S mutation, while SNS-062 was not.

The investigators said SNS-062 was 6 times more potent than ibrutinib against C481S BTK and more than 640 times more potent than acalabrutinib.

The team also noted that SNS-062 exhibited high specificity, affecting a limited number of kinases outside the TEC kinase family.

Finally, the investigators found that SNS-062 diminished stromal cell protection in CLL cells, suggesting the drug can hinder protection from the tumor microenvironment.

Micrograph showing CLL

WASHINGTON, DC—Preclinical research suggests a second-generation BTK inhibitor may overcome the acquired resistance observed with its predecessor in patients with chronic lymphocytic leukemia (CLL).

Investigators found the non-covalent BTK inhibitor SNS-062 was unaffected by the BTK C481S mutation, which confers resistance to the first-generation BTK inhibitor ibrutinib.

“[A] subset of patients acquire resistance to ibrutinib, the current standard-of-care BTK inhibitor,” said Amy Johnson, PhD, of The Ohio State University in Columbus.

“A key resistance mechanism to covalent BTK inhibitors is a point mutation in the BTK active site, converting cysteine 481 to serine, or C481S.”

“In this study, we demonstrate that SNS-062, which binds non-covalently to BTK, is a potent inhibitor of BTK unaffected by the presence of the C481S mutation. These findings support clinical investigation of SNS-062 to address acquired resistance to covalent BTK inhibitors in patients.”

Dr Johnson and her colleagues presented these findings at the AACR Annual Meeting 2017 (abstract 1207).

SNS-062 is being developed by Sunesis Pharmaceuticals, Inc., and company investigators were involved in this research. But the study was sponsored by The Ohio State University.

For this study, Dr Johnson and her colleagues tested SNS-062 in primary CLL cells and X-linked agammaglobulinemia human cell lines.

The investigators found that SNS-062 inhibited BTK, decreased the expression of B-cell activation markers, and reduced CLL cell viability in a dose-dependent manner. And these effects were comparable to those observed with ibrutinib.

SNS-062 and ibrutinib demonstrated comparable activity against wild-type BTK. However, ibrutinib and another BTK inhibitor, acalabrutinib, were hindered by the BTK C481S mutation, while SNS-062 was not.

The investigators said SNS-062 was 6 times more potent than ibrutinib against C481S BTK and more than 640 times more potent than acalabrutinib.

The team also noted that SNS-062 exhibited high specificity, affecting a limited number of kinases outside the TEC kinase family.

Finally, the investigators found that SNS-062 diminished stromal cell protection in CLL cells, suggesting the drug can hinder protection from the tumor microenvironment.

Micrograph showing CLL

WASHINGTON, DC—Preclinical research suggests a second-generation BTK inhibitor may overcome the acquired resistance observed with its predecessor in patients with chronic lymphocytic leukemia (CLL).

Investigators found the non-covalent BTK inhibitor SNS-062 was unaffected by the BTK C481S mutation, which confers resistance to the first-generation BTK inhibitor ibrutinib.

“[A] subset of patients acquire resistance to ibrutinib, the current standard-of-care BTK inhibitor,” said Amy Johnson, PhD, of The Ohio State University in Columbus.

“A key resistance mechanism to covalent BTK inhibitors is a point mutation in the BTK active site, converting cysteine 481 to serine, or C481S.”

“In this study, we demonstrate that SNS-062, which binds non-covalently to BTK, is a potent inhibitor of BTK unaffected by the presence of the C481S mutation. These findings support clinical investigation of SNS-062 to address acquired resistance to covalent BTK inhibitors in patients.”

Dr Johnson and her colleagues presented these findings at the AACR Annual Meeting 2017 (abstract 1207).

SNS-062 is being developed by Sunesis Pharmaceuticals, Inc., and company investigators were involved in this research. But the study was sponsored by The Ohio State University.

For this study, Dr Johnson and her colleagues tested SNS-062 in primary CLL cells and X-linked agammaglobulinemia human cell lines.

The investigators found that SNS-062 inhibited BTK, decreased the expression of B-cell activation markers, and reduced CLL cell viability in a dose-dependent manner. And these effects were comparable to those observed with ibrutinib.

SNS-062 and ibrutinib demonstrated comparable activity against wild-type BTK. However, ibrutinib and another BTK inhibitor, acalabrutinib, were hindered by the BTK C481S mutation, while SNS-062 was not.

The investigators said SNS-062 was 6 times more potent than ibrutinib against C481S BTK and more than 640 times more potent than acalabrutinib.

The team also noted that SNS-062 exhibited high specificity, affecting a limited number of kinases outside the TEC kinase family.

Finally, the investigators found that SNS-062 diminished stromal cell protection in CLL cells, suggesting the drug can hinder protection from the tumor microenvironment.