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Reduced-intensity conditioning may not preserve fertility in young girls after bone marrow transplant
ORLANDO – Girls who undergo reduced-intensity conditioning for a bone marrow transplant may face fertility problems in the future, even if they experience an outwardly normal puberty.
In the first-ever study to compare high- and low-intensity chemotherapeutic conditioning regimens among young girls, significantly more who underwent the reduced-intensity regimen had normal estradiol, luteinizing hormone, and follicle-stimulating hormone compared with those who had high-intensity conditioning. But anti-Müllerian hormone was low or absent in almost all the girls, no matter which conditioning regimen they had, Jonathan C. Howell, MD, PhD, said at the annual meeting of the Endocrine Society.
While not a perfect predictor of future fertility, anti-Müllerian hormone is a good indicator of ovarian follicular reserve, said Dr. Howell, a pediatric endocrinologist at Cincinnati Children’s Hospital Medical Center.
Dr. Howell and his colleagues, Holly R. Hoefgen, MD, Kasiani C. Myers, MD, and Helen Oquendo-Del Toro, MD, all of Cincinnati Children’s Hospital Medical Center, are following 49 females aged 1-40 years who had preconditioning chemotherapy in advance of hematopoietic stem cell transplantation.
At the meeting, Dr. Howell reported data on 23 girls who were in puberty during their treatment (mean age 12 years). The mean follow-up was 4 years, but this varied widely, from 1 to 13 years. Most (16) had high-intensity myeloablation; the remainder had reduced-intensity conditioning. Diagnoses varied between the groups. Among those with high-intensity conditioning, malignancy and bone marrow failure were the most common indications (seven patients each); one patient had an immunodeficiency, and the cause was unknown for another.
Among those who had the reduced-intensity regimen, five had an immunodeficiency and two had bone marrow failure.
The discrepancy in diagnoses between the groups isn’t surprising, Dr. Howell said. “Diagnosis can dictate which treatment patients receive. People with malignancies or a prior history of leukemia or lymphoma often receive the high-intensity conditioning. You want to wipe out every single malignant cell.”
Reduced-intensity conditioning may be an option for patients with other problems such as bone marrow failure, immunodeficiencies, or genetic or metabolic problems. The less-intense regimen does confer some benefits, Dr. Howell noted. “The short-term need for intensive medical therapy while getting the stem cells is less. The medical benefit of these less-intense regimens is certainly there, but the long-term endocrine impact has yet to be defined.”
Most of the girls in the high-intensity regimen group (64%) had high follicle stimulating hormone and luteinizing hormone, suggesting primary ovarian failure; 71% of them also had low estradiol levels. However, all of these hormones were normal in the reduced-intensity group. But regardless of conditioning treatment, anti-Müllerian hormone was abnormally low in nearly all of the patients (87%). Only one girl with myeloablative conditioning and two girls with reduced intensity condition had normal anti-Müllerian levels. “This tells us that fertility potential may not be preserved, despite [their] getting the reduced-intensity conditioning,” Dr. Howell said.
The story here is only beginning to unfold, he said. “Fertility is defined as the ability to conceive a child, and that’s not something we have looked at yet. We would like to know the long-term outcomes of fertility in these patients, and whether they can conceive when they’re ready to start a family. Our goal is to follow these young women into their 20s and 30s, and to see if that’s an opportunity they are able to experience.”
The study is a cooperative project involving the hospital’s divisions of Pediatric and Adolescent Gynecology, Bone Marrow Transplantation and Immunology, and Endocrinology.
Neither Dr. Howell nor any of his colleagues had any financial disclosures.
Fertility preservation talks: The earlier, the better
A talk about fertility preservation can be the first step into a new future for families of children with a cancer diagnosis.
“Talking about your baby having a baby can be the farthest thing from your mind,” when you’re the parent of a child about to undergo cancer treatment, said Dr. Hoefgen. “But we know from survivors that this can be a very important issue in the future. We simply start by telling parents, ‘This will be important to your child at some point, and we want to talk about it now, while there is still something we may be able to do about it.’ ”
Dr. Hoefgen, a staff member at the hospital’s Comprehensive Fertility Care and Preservation Program, said parents “sometimes find it weird” to be talking about unborn grandchildren when they’re consumed with making critical decisions for their own child. But by asking them to consider that child’s long-term future, the discussion offers its own message of hope.
The talks always begin with a basic discussion of how cancer treatments can affect the reproductive organs. The hospital has a series of short animated videos that are very helpful in relaying the information. Another video in that series describes the different methods of fertility preservation: mature oocyte or sperm harvesting, or, for younger patients, removing and freezing ovarian and testicular tissue. Parents and children can watch them together, get grounding in the basics, and be prepared for a productive conversation.
Talks always include the team oncologist, who creates a specialized risk assessment for each patient. The group discusses each preservation method, the risks and benefits, and the cost. But the talks are exploratory, too, helping both clinicians and families understand what’s most important to them, she said.
“Common things that we typically talk about are genetics, religion, and ethics – which may mean different things to different families.”
Dr. Hoefgen and her team reach out to more than 95% of families that face a pediatric cancer diagnosis. After the in-depth discussions, she said, about 20% decide to investigate some form of fertility preservation.
“The most important thing is having the conversation early, while we still have options,” she said.
Dr. Hoefgen had no financial disclosures.
ORLANDO – Girls who undergo reduced-intensity conditioning for a bone marrow transplant may face fertility problems in the future, even if they experience an outwardly normal puberty.
In the first-ever study to compare high- and low-intensity chemotherapeutic conditioning regimens among young girls, significantly more who underwent the reduced-intensity regimen had normal estradiol, luteinizing hormone, and follicle-stimulating hormone compared with those who had high-intensity conditioning. But anti-Müllerian hormone was low or absent in almost all the girls, no matter which conditioning regimen they had, Jonathan C. Howell, MD, PhD, said at the annual meeting of the Endocrine Society.
While not a perfect predictor of future fertility, anti-Müllerian hormone is a good indicator of ovarian follicular reserve, said Dr. Howell, a pediatric endocrinologist at Cincinnati Children’s Hospital Medical Center.
Dr. Howell and his colleagues, Holly R. Hoefgen, MD, Kasiani C. Myers, MD, and Helen Oquendo-Del Toro, MD, all of Cincinnati Children’s Hospital Medical Center, are following 49 females aged 1-40 years who had preconditioning chemotherapy in advance of hematopoietic stem cell transplantation.
At the meeting, Dr. Howell reported data on 23 girls who were in puberty during their treatment (mean age 12 years). The mean follow-up was 4 years, but this varied widely, from 1 to 13 years. Most (16) had high-intensity myeloablation; the remainder had reduced-intensity conditioning. Diagnoses varied between the groups. Among those with high-intensity conditioning, malignancy and bone marrow failure were the most common indications (seven patients each); one patient had an immunodeficiency, and the cause was unknown for another.
Among those who had the reduced-intensity regimen, five had an immunodeficiency and two had bone marrow failure.
The discrepancy in diagnoses between the groups isn’t surprising, Dr. Howell said. “Diagnosis can dictate which treatment patients receive. People with malignancies or a prior history of leukemia or lymphoma often receive the high-intensity conditioning. You want to wipe out every single malignant cell.”
Reduced-intensity conditioning may be an option for patients with other problems such as bone marrow failure, immunodeficiencies, or genetic or metabolic problems. The less-intense regimen does confer some benefits, Dr. Howell noted. “The short-term need for intensive medical therapy while getting the stem cells is less. The medical benefit of these less-intense regimens is certainly there, but the long-term endocrine impact has yet to be defined.”
Most of the girls in the high-intensity regimen group (64%) had high follicle stimulating hormone and luteinizing hormone, suggesting primary ovarian failure; 71% of them also had low estradiol levels. However, all of these hormones were normal in the reduced-intensity group. But regardless of conditioning treatment, anti-Müllerian hormone was abnormally low in nearly all of the patients (87%). Only one girl with myeloablative conditioning and two girls with reduced intensity condition had normal anti-Müllerian levels. “This tells us that fertility potential may not be preserved, despite [their] getting the reduced-intensity conditioning,” Dr. Howell said.
The story here is only beginning to unfold, he said. “Fertility is defined as the ability to conceive a child, and that’s not something we have looked at yet. We would like to know the long-term outcomes of fertility in these patients, and whether they can conceive when they’re ready to start a family. Our goal is to follow these young women into their 20s and 30s, and to see if that’s an opportunity they are able to experience.”
The study is a cooperative project involving the hospital’s divisions of Pediatric and Adolescent Gynecology, Bone Marrow Transplantation and Immunology, and Endocrinology.
Neither Dr. Howell nor any of his colleagues had any financial disclosures.
Fertility preservation talks: The earlier, the better
A talk about fertility preservation can be the first step into a new future for families of children with a cancer diagnosis.
“Talking about your baby having a baby can be the farthest thing from your mind,” when you’re the parent of a child about to undergo cancer treatment, said Dr. Hoefgen. “But we know from survivors that this can be a very important issue in the future. We simply start by telling parents, ‘This will be important to your child at some point, and we want to talk about it now, while there is still something we may be able to do about it.’ ”
Dr. Hoefgen, a staff member at the hospital’s Comprehensive Fertility Care and Preservation Program, said parents “sometimes find it weird” to be talking about unborn grandchildren when they’re consumed with making critical decisions for their own child. But by asking them to consider that child’s long-term future, the discussion offers its own message of hope.
The talks always begin with a basic discussion of how cancer treatments can affect the reproductive organs. The hospital has a series of short animated videos that are very helpful in relaying the information. Another video in that series describes the different methods of fertility preservation: mature oocyte or sperm harvesting, or, for younger patients, removing and freezing ovarian and testicular tissue. Parents and children can watch them together, get grounding in the basics, and be prepared for a productive conversation.
Talks always include the team oncologist, who creates a specialized risk assessment for each patient. The group discusses each preservation method, the risks and benefits, and the cost. But the talks are exploratory, too, helping both clinicians and families understand what’s most important to them, she said.
“Common things that we typically talk about are genetics, religion, and ethics – which may mean different things to different families.”
Dr. Hoefgen and her team reach out to more than 95% of families that face a pediatric cancer diagnosis. After the in-depth discussions, she said, about 20% decide to investigate some form of fertility preservation.
“The most important thing is having the conversation early, while we still have options,” she said.
Dr. Hoefgen had no financial disclosures.
ORLANDO – Girls who undergo reduced-intensity conditioning for a bone marrow transplant may face fertility problems in the future, even if they experience an outwardly normal puberty.
In the first-ever study to compare high- and low-intensity chemotherapeutic conditioning regimens among young girls, significantly more who underwent the reduced-intensity regimen had normal estradiol, luteinizing hormone, and follicle-stimulating hormone compared with those who had high-intensity conditioning. But anti-Müllerian hormone was low or absent in almost all the girls, no matter which conditioning regimen they had, Jonathan C. Howell, MD, PhD, said at the annual meeting of the Endocrine Society.
While not a perfect predictor of future fertility, anti-Müllerian hormone is a good indicator of ovarian follicular reserve, said Dr. Howell, a pediatric endocrinologist at Cincinnati Children’s Hospital Medical Center.
Dr. Howell and his colleagues, Holly R. Hoefgen, MD, Kasiani C. Myers, MD, and Helen Oquendo-Del Toro, MD, all of Cincinnati Children’s Hospital Medical Center, are following 49 females aged 1-40 years who had preconditioning chemotherapy in advance of hematopoietic stem cell transplantation.
At the meeting, Dr. Howell reported data on 23 girls who were in puberty during their treatment (mean age 12 years). The mean follow-up was 4 years, but this varied widely, from 1 to 13 years. Most (16) had high-intensity myeloablation; the remainder had reduced-intensity conditioning. Diagnoses varied between the groups. Among those with high-intensity conditioning, malignancy and bone marrow failure were the most common indications (seven patients each); one patient had an immunodeficiency, and the cause was unknown for another.
Among those who had the reduced-intensity regimen, five had an immunodeficiency and two had bone marrow failure.
The discrepancy in diagnoses between the groups isn’t surprising, Dr. Howell said. “Diagnosis can dictate which treatment patients receive. People with malignancies or a prior history of leukemia or lymphoma often receive the high-intensity conditioning. You want to wipe out every single malignant cell.”
Reduced-intensity conditioning may be an option for patients with other problems such as bone marrow failure, immunodeficiencies, or genetic or metabolic problems. The less-intense regimen does confer some benefits, Dr. Howell noted. “The short-term need for intensive medical therapy while getting the stem cells is less. The medical benefit of these less-intense regimens is certainly there, but the long-term endocrine impact has yet to be defined.”
Most of the girls in the high-intensity regimen group (64%) had high follicle stimulating hormone and luteinizing hormone, suggesting primary ovarian failure; 71% of them also had low estradiol levels. However, all of these hormones were normal in the reduced-intensity group. But regardless of conditioning treatment, anti-Müllerian hormone was abnormally low in nearly all of the patients (87%). Only one girl with myeloablative conditioning and two girls with reduced intensity condition had normal anti-Müllerian levels. “This tells us that fertility potential may not be preserved, despite [their] getting the reduced-intensity conditioning,” Dr. Howell said.
The story here is only beginning to unfold, he said. “Fertility is defined as the ability to conceive a child, and that’s not something we have looked at yet. We would like to know the long-term outcomes of fertility in these patients, and whether they can conceive when they’re ready to start a family. Our goal is to follow these young women into their 20s and 30s, and to see if that’s an opportunity they are able to experience.”
The study is a cooperative project involving the hospital’s divisions of Pediatric and Adolescent Gynecology, Bone Marrow Transplantation and Immunology, and Endocrinology.
Neither Dr. Howell nor any of his colleagues had any financial disclosures.
Fertility preservation talks: The earlier, the better
A talk about fertility preservation can be the first step into a new future for families of children with a cancer diagnosis.
“Talking about your baby having a baby can be the farthest thing from your mind,” when you’re the parent of a child about to undergo cancer treatment, said Dr. Hoefgen. “But we know from survivors that this can be a very important issue in the future. We simply start by telling parents, ‘This will be important to your child at some point, and we want to talk about it now, while there is still something we may be able to do about it.’ ”
Dr. Hoefgen, a staff member at the hospital’s Comprehensive Fertility Care and Preservation Program, said parents “sometimes find it weird” to be talking about unborn grandchildren when they’re consumed with making critical decisions for their own child. But by asking them to consider that child’s long-term future, the discussion offers its own message of hope.
The talks always begin with a basic discussion of how cancer treatments can affect the reproductive organs. The hospital has a series of short animated videos that are very helpful in relaying the information. Another video in that series describes the different methods of fertility preservation: mature oocyte or sperm harvesting, or, for younger patients, removing and freezing ovarian and testicular tissue. Parents and children can watch them together, get grounding in the basics, and be prepared for a productive conversation.
Talks always include the team oncologist, who creates a specialized risk assessment for each patient. The group discusses each preservation method, the risks and benefits, and the cost. But the talks are exploratory, too, helping both clinicians and families understand what’s most important to them, she said.
“Common things that we typically talk about are genetics, religion, and ethics – which may mean different things to different families.”
Dr. Hoefgen and her team reach out to more than 95% of families that face a pediatric cancer diagnosis. After the in-depth discussions, she said, about 20% decide to investigate some form of fertility preservation.
“The most important thing is having the conversation early, while we still have options,” she said.
Dr. Hoefgen had no financial disclosures.
AT ENDO 2017
Key clinical point:
Major finding: Anti-Müllerian hormone was abnormally low or absent in all treated girls, whether they had reduced-intensity or high-intensity conditioning.
Data source: The prospective study is following 49 females aged 1-40 years.
Disclosures: Neither Dr. Howell nor any of his colleagues had any financial disclosures.
Three factors linked to rhinovirus pneumonia in HCT patients
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
AT THE BMT TANDEM MEETINGS
Key clinical point:
Major finding: Of 3,445 HCT patients, 732 patients (21%) were positive for human rhinovirus.
Data source: Single-center, 6-year retrospective study of 732 HCT patients with human rhinovirus infection.
Disclosures: Dr. Waghmare reported receiving research funding from Aviragen, the maker of vapendavir, an investigational drug for human rhinovirus infection, and Gilead Sciences.
Transplantation plus VRD tops VRD alone in myeloma
Adding high-dose chemotherapy and autologous stem cell transplantation to two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) significantly improved progression-free survival in adults with newly diagnosed multiple myeloma, according to new analyses from the multicenter, randomized, phase III IFM 2009 Study.
Median PFS was 50 months in the transplantation group, versus 36 months when patients only received five cycles of VRD for consolidation (adjusted hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.53 to 0.80; P less than .001), reported Michel Attal, MD, of Institut Universitaire du Cancer de Toulouse-Oncopole in Toulouse, France, and his associates. “Transplantation was also associated with a higher rate of complete response, a lower rate of minimal residual disease detection, and a longer median time to progression,” they wrote (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMoa1611750).
Transplantation did not improve 4-year overall survival (81% with transplantation plus VRD and 82% with VRD only), perhaps because VRD-only patients had the option of salvage transplantation if their disease progressed, the investigators said. In addition, grade 3 or 4 neutropenias were significantly more common with transplantation than otherwise (92% versus 47%), as were grade 3 or 4 gastrointestinal disorders (28% versus 7%) and infections (20% versus 9%). However, the groups did not significantly differ in terms of treatment-related deaths, second primary cancers, thromboembolic events, or peripheral neuropathy.
Before the advent of immunomodulatory drugs and proteasome inhibitors, several randomized trials showed that the benefits of high-dose chemotherapy with autologous stem cell transplantation outperformed conventional chemotherapy in multiple myeloma. For IFM 2009, 700 newly diagnosed patients aged up to 65 years received three 21-day cycles of VRD induction: bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; lenalidomide 25 mg on days 1-14; and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Consolidation consisted of either five more VRD cycles with dexamethasone reduced to 10 mg/day, or high-dose (200 mg/m2) melphalan plus transplantation followed by two VRD cycles with the reduced dexamethasone dose. Both arms received 1 year of lenalidomide maintenance (10 mg/day for 3 months, followed by 15/mg day, depending on side effects).
Transplantation was associated with a significantly higher likelihood of complete response (59% versus 48%; P = .03) and undetectable minimal residual disease (79% versus 65%; P less than .001). Undetectable minimal residual disease, in turn, predicted longer PFS (adjusted hazard ratio, 0.30; P = .001). In contrast, age, sex, isotype of the monoclonal component, International Staging System disease stage, and cytogenetic risk profile did not significantly affect PFS among transplant patients.
The PFS benefit of transplantation “must be weighed against the increased risk of toxic effects associated with high-dose chemotherapy plus transplantation, especially since we found that later transplantation might be as effective as early transplantation in securing long- term survival,” the researchers said. “Our results suggest that the use of a combination therapy that incorporates newer proteasome inhibitors, next-generation immunomodulatory drugs, and potent monoclonal antibodies along with transplantation tailored according to minimal residual disease detection could further improve outcomes among adults up to 65 years of age who have multiple myeloma.”
Celgene, Janssen, the French Ministry of Health Programme Hospitalier de Recherche Clinique, and the French National Research Agency funded the study. Dr. Attal had no conflicts. Nine coinvestigators disclosed ties to Celgene, Janssen, and several other pharmaceutical companies. Two coinvestigators disclosed ownership or founder roles in OncoPep, one of whom disclosed patent licensure to OncoPep for a multipeptide vaccine. The other investigators had no conflicts.
In the IFM 2009 trial, the planned treatments were realistic. The combination of immunomodulatory drugs and proteasome inhibitors is associated with high response rates similar to those achieved with transplantation, whereas previous trials had used less effective chemotherapy regimens as comparators.
[Transplantation] resulted in a deeper and longer initial treatment response than did nontransplantation. However, the benefits of transplantation were more modest than some might have hoped, and it did not appear to be curative.
A question remains as to whether all patients with multiple myeloma should undergo immediate autologous stem-cell transplantation, since the use of delayed transplantation resulted in similar overall survival, with some patients not needing transplantation to date. The observed lack of a survival benefit for early transplantation was consistent with previous results that suggested salvage transplantation is an equalizer in this regard.
Charles A. Schiffer, MD, and Jeffrey A. Zonder, MD, are with Karmanos Cancer Institute, Wayne State University, Detroit, Mich. Dr. Zonder is a member of the editorial advisory board of Hematology News. Their comments were taken from an editorial (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMe1700453).
In the IFM 2009 trial, the planned treatments were realistic. The combination of immunomodulatory drugs and proteasome inhibitors is associated with high response rates similar to those achieved with transplantation, whereas previous trials had used less effective chemotherapy regimens as comparators.
[Transplantation] resulted in a deeper and longer initial treatment response than did nontransplantation. However, the benefits of transplantation were more modest than some might have hoped, and it did not appear to be curative.
A question remains as to whether all patients with multiple myeloma should undergo immediate autologous stem-cell transplantation, since the use of delayed transplantation resulted in similar overall survival, with some patients not needing transplantation to date. The observed lack of a survival benefit for early transplantation was consistent with previous results that suggested salvage transplantation is an equalizer in this regard.
Charles A. Schiffer, MD, and Jeffrey A. Zonder, MD, are with Karmanos Cancer Institute, Wayne State University, Detroit, Mich. Dr. Zonder is a member of the editorial advisory board of Hematology News. Their comments were taken from an editorial (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMe1700453).
In the IFM 2009 trial, the planned treatments were realistic. The combination of immunomodulatory drugs and proteasome inhibitors is associated with high response rates similar to those achieved with transplantation, whereas previous trials had used less effective chemotherapy regimens as comparators.
[Transplantation] resulted in a deeper and longer initial treatment response than did nontransplantation. However, the benefits of transplantation were more modest than some might have hoped, and it did not appear to be curative.
A question remains as to whether all patients with multiple myeloma should undergo immediate autologous stem-cell transplantation, since the use of delayed transplantation resulted in similar overall survival, with some patients not needing transplantation to date. The observed lack of a survival benefit for early transplantation was consistent with previous results that suggested salvage transplantation is an equalizer in this regard.
Charles A. Schiffer, MD, and Jeffrey A. Zonder, MD, are with Karmanos Cancer Institute, Wayne State University, Detroit, Mich. Dr. Zonder is a member of the editorial advisory board of Hematology News. Their comments were taken from an editorial (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMe1700453).
Adding high-dose chemotherapy and autologous stem cell transplantation to two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) significantly improved progression-free survival in adults with newly diagnosed multiple myeloma, according to new analyses from the multicenter, randomized, phase III IFM 2009 Study.
Median PFS was 50 months in the transplantation group, versus 36 months when patients only received five cycles of VRD for consolidation (adjusted hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.53 to 0.80; P less than .001), reported Michel Attal, MD, of Institut Universitaire du Cancer de Toulouse-Oncopole in Toulouse, France, and his associates. “Transplantation was also associated with a higher rate of complete response, a lower rate of minimal residual disease detection, and a longer median time to progression,” they wrote (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMoa1611750).
Transplantation did not improve 4-year overall survival (81% with transplantation plus VRD and 82% with VRD only), perhaps because VRD-only patients had the option of salvage transplantation if their disease progressed, the investigators said. In addition, grade 3 or 4 neutropenias were significantly more common with transplantation than otherwise (92% versus 47%), as were grade 3 or 4 gastrointestinal disorders (28% versus 7%) and infections (20% versus 9%). However, the groups did not significantly differ in terms of treatment-related deaths, second primary cancers, thromboembolic events, or peripheral neuropathy.
Before the advent of immunomodulatory drugs and proteasome inhibitors, several randomized trials showed that the benefits of high-dose chemotherapy with autologous stem cell transplantation outperformed conventional chemotherapy in multiple myeloma. For IFM 2009, 700 newly diagnosed patients aged up to 65 years received three 21-day cycles of VRD induction: bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; lenalidomide 25 mg on days 1-14; and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Consolidation consisted of either five more VRD cycles with dexamethasone reduced to 10 mg/day, or high-dose (200 mg/m2) melphalan plus transplantation followed by two VRD cycles with the reduced dexamethasone dose. Both arms received 1 year of lenalidomide maintenance (10 mg/day for 3 months, followed by 15/mg day, depending on side effects).
Transplantation was associated with a significantly higher likelihood of complete response (59% versus 48%; P = .03) and undetectable minimal residual disease (79% versus 65%; P less than .001). Undetectable minimal residual disease, in turn, predicted longer PFS (adjusted hazard ratio, 0.30; P = .001). In contrast, age, sex, isotype of the monoclonal component, International Staging System disease stage, and cytogenetic risk profile did not significantly affect PFS among transplant patients.
The PFS benefit of transplantation “must be weighed against the increased risk of toxic effects associated with high-dose chemotherapy plus transplantation, especially since we found that later transplantation might be as effective as early transplantation in securing long- term survival,” the researchers said. “Our results suggest that the use of a combination therapy that incorporates newer proteasome inhibitors, next-generation immunomodulatory drugs, and potent monoclonal antibodies along with transplantation tailored according to minimal residual disease detection could further improve outcomes among adults up to 65 years of age who have multiple myeloma.”
Celgene, Janssen, the French Ministry of Health Programme Hospitalier de Recherche Clinique, and the French National Research Agency funded the study. Dr. Attal had no conflicts. Nine coinvestigators disclosed ties to Celgene, Janssen, and several other pharmaceutical companies. Two coinvestigators disclosed ownership or founder roles in OncoPep, one of whom disclosed patent licensure to OncoPep for a multipeptide vaccine. The other investigators had no conflicts.
Adding high-dose chemotherapy and autologous stem cell transplantation to two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) significantly improved progression-free survival in adults with newly diagnosed multiple myeloma, according to new analyses from the multicenter, randomized, phase III IFM 2009 Study.
Median PFS was 50 months in the transplantation group, versus 36 months when patients only received five cycles of VRD for consolidation (adjusted hazard ratio for disease progression or death, 0.65; 95% confidence interval, 0.53 to 0.80; P less than .001), reported Michel Attal, MD, of Institut Universitaire du Cancer de Toulouse-Oncopole in Toulouse, France, and his associates. “Transplantation was also associated with a higher rate of complete response, a lower rate of minimal residual disease detection, and a longer median time to progression,” they wrote (N Engl J Med. 2017 April 6. doi: 10.1056/NEJMoa1611750).
Transplantation did not improve 4-year overall survival (81% with transplantation plus VRD and 82% with VRD only), perhaps because VRD-only patients had the option of salvage transplantation if their disease progressed, the investigators said. In addition, grade 3 or 4 neutropenias were significantly more common with transplantation than otherwise (92% versus 47%), as were grade 3 or 4 gastrointestinal disorders (28% versus 7%) and infections (20% versus 9%). However, the groups did not significantly differ in terms of treatment-related deaths, second primary cancers, thromboembolic events, or peripheral neuropathy.
Before the advent of immunomodulatory drugs and proteasome inhibitors, several randomized trials showed that the benefits of high-dose chemotherapy with autologous stem cell transplantation outperformed conventional chemotherapy in multiple myeloma. For IFM 2009, 700 newly diagnosed patients aged up to 65 years received three 21-day cycles of VRD induction: bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11; lenalidomide 25 mg on days 1-14; and dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12. Consolidation consisted of either five more VRD cycles with dexamethasone reduced to 10 mg/day, or high-dose (200 mg/m2) melphalan plus transplantation followed by two VRD cycles with the reduced dexamethasone dose. Both arms received 1 year of lenalidomide maintenance (10 mg/day for 3 months, followed by 15/mg day, depending on side effects).
Transplantation was associated with a significantly higher likelihood of complete response (59% versus 48%; P = .03) and undetectable minimal residual disease (79% versus 65%; P less than .001). Undetectable minimal residual disease, in turn, predicted longer PFS (adjusted hazard ratio, 0.30; P = .001). In contrast, age, sex, isotype of the monoclonal component, International Staging System disease stage, and cytogenetic risk profile did not significantly affect PFS among transplant patients.
The PFS benefit of transplantation “must be weighed against the increased risk of toxic effects associated with high-dose chemotherapy plus transplantation, especially since we found that later transplantation might be as effective as early transplantation in securing long- term survival,” the researchers said. “Our results suggest that the use of a combination therapy that incorporates newer proteasome inhibitors, next-generation immunomodulatory drugs, and potent monoclonal antibodies along with transplantation tailored according to minimal residual disease detection could further improve outcomes among adults up to 65 years of age who have multiple myeloma.”
Celgene, Janssen, the French Ministry of Health Programme Hospitalier de Recherche Clinique, and the French National Research Agency funded the study. Dr. Attal had no conflicts. Nine coinvestigators disclosed ties to Celgene, Janssen, and several other pharmaceutical companies. Two coinvestigators disclosed ownership or founder roles in OncoPep, one of whom disclosed patent licensure to OncoPep for a multipeptide vaccine. The other investigators had no conflicts.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: High-dose chemotherapy and autologous stem cell transplantation plus bortezomib, lenalidomide, and dexamethasone (VRD) outperformed consolidation with VRD only in adults with newly diagnosed multiple myeloma.
Major finding: Median progression-free survival was 50 months with transplantation plus VRD and 36 months with VRD only (adjusted hazard ratio for disease progression or death, 0.65; P less than .001).
Data source: A randomized, multicenter, open-label, phase III trial of 700 patients with multiple myeloma.
Disclosures: Celgene, Janssen, the French Ministry of Health Programme Hospitalier de Recherche Clinique, and the French National Research Agency funded the study. Dr. Attal had no conflicts. Nine coinvestigators disclosed ties to Celgene, Janssen, and several other pharmaceutical companies. Two coinvestigators disclosed ownership or founder roles in OncoPep, one of whom disclosed patent licensure to OncoPep for a multipeptide vaccine. The other investigators had no conflicts.
Cell sheet transplantation improves ischemic cardiomyopathy at 1 year
For patients with ischemic cardiomyopathy (ICM), transplanting sheets of autologous myoblasts onto the epicardial surface was safe and led to “marked” improvements in functional and laboratory measures, investigators reported.
However, cell sheet transplantation was much less effective for patients with dilated cardiomyopathy in this phase I trial, wrote Shigeru Miyagawa, MD, PhD, of Osaka (Japan) University, and his associates in the Journal of the American Heart Association. The findings merit additional follow-up in larger clinical studies, the investigators asserted.
Heart failure remains life threatening even with the best approved treatments. Previously, the researchers transplanted scaffold-free sheets of autologous myoblasts derived from skeletal muscle into small and large animals with heart failure and found that this approach healed severely damaged myocardium. Transplantation caused secreted cytokines to induce native regeneration through paracrine effects, Dr. Miyagawa noted in a prior review article (BioMed Research International. 2013. doi: 10.1155/2013/583912).
To evaluate this approach in humans, the researchers transplanted 15 patients with ischemic cardiomyopathy and 12 patients with dilated cardiomyopathy (DCM). Patients were 20-75 years old, had ejection fractions under 35% and New York Heart Association (NYHA) classifications of II or more, and were responding inadequately to standard treatment with a beta-blocker or ACE inhibitor and an angiotensin receptor blocker. The sole intervention was transplantation of the cell sheet over the left ventricular-free wall during left thoracotomy (J Am Heart Assoc. 2017 Apr 5. doi: 10.1161/JAHA.116.003918). There were no major procedure-related complications during follow-up, the researchers said. For patients with ICM, NYHA classifications dropped significantly at 6 months, from 2.9 at baseline to 2.1 at 6 months and 1.9 at 1 year. Six-Minute Walk Test scores improved significantly, from 416 m at baseline to 475 m at 6 months to 484 m at 1 year. Transplantation also led to significant drops in serum brain natriuretic peptide levels (baseline average, 308 pg/mL; 6 months, 191 pg/mL; 1 year, 182 pg/mL). Additionally, ICM patients improved significantly on measures of pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary vein resistance, and left ventricular wall stress.
In contrast, DCM patients did not significantly improve based on the 6-Minute Walk Test, NYHA classification, or brain natriuretic peptide serum levels. Of 12, 3 progressed to NYHA functional class IV by 1-year follow-up and there were five cardiac deaths. There were no cardiac deaths in the ICM group. “It has been reported that regeneration mechanisms in cell sheet mainly depend on angiogenesis induced by secreted cytokines, so cell-sheet implantation may be more suitable for ICM patients, compared with DCM patients, considering pathophysiological aspects,” the researchers wrote.
The study was funded by grants from Regenerative Medicine for Clinical Application, Health and Labor Sciences Research, and the Japan Agency for Medical Research and Development. The investigators disclosed laboratory funding from Terumo for cooperative research in cell sheet.
For patients with ischemic cardiomyopathy (ICM), transplanting sheets of autologous myoblasts onto the epicardial surface was safe and led to “marked” improvements in functional and laboratory measures, investigators reported.
However, cell sheet transplantation was much less effective for patients with dilated cardiomyopathy in this phase I trial, wrote Shigeru Miyagawa, MD, PhD, of Osaka (Japan) University, and his associates in the Journal of the American Heart Association. The findings merit additional follow-up in larger clinical studies, the investigators asserted.
Heart failure remains life threatening even with the best approved treatments. Previously, the researchers transplanted scaffold-free sheets of autologous myoblasts derived from skeletal muscle into small and large animals with heart failure and found that this approach healed severely damaged myocardium. Transplantation caused secreted cytokines to induce native regeneration through paracrine effects, Dr. Miyagawa noted in a prior review article (BioMed Research International. 2013. doi: 10.1155/2013/583912).
To evaluate this approach in humans, the researchers transplanted 15 patients with ischemic cardiomyopathy and 12 patients with dilated cardiomyopathy (DCM). Patients were 20-75 years old, had ejection fractions under 35% and New York Heart Association (NYHA) classifications of II or more, and were responding inadequately to standard treatment with a beta-blocker or ACE inhibitor and an angiotensin receptor blocker. The sole intervention was transplantation of the cell sheet over the left ventricular-free wall during left thoracotomy (J Am Heart Assoc. 2017 Apr 5. doi: 10.1161/JAHA.116.003918). There were no major procedure-related complications during follow-up, the researchers said. For patients with ICM, NYHA classifications dropped significantly at 6 months, from 2.9 at baseline to 2.1 at 6 months and 1.9 at 1 year. Six-Minute Walk Test scores improved significantly, from 416 m at baseline to 475 m at 6 months to 484 m at 1 year. Transplantation also led to significant drops in serum brain natriuretic peptide levels (baseline average, 308 pg/mL; 6 months, 191 pg/mL; 1 year, 182 pg/mL). Additionally, ICM patients improved significantly on measures of pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary vein resistance, and left ventricular wall stress.
In contrast, DCM patients did not significantly improve based on the 6-Minute Walk Test, NYHA classification, or brain natriuretic peptide serum levels. Of 12, 3 progressed to NYHA functional class IV by 1-year follow-up and there were five cardiac deaths. There were no cardiac deaths in the ICM group. “It has been reported that regeneration mechanisms in cell sheet mainly depend on angiogenesis induced by secreted cytokines, so cell-sheet implantation may be more suitable for ICM patients, compared with DCM patients, considering pathophysiological aspects,” the researchers wrote.
The study was funded by grants from Regenerative Medicine for Clinical Application, Health and Labor Sciences Research, and the Japan Agency for Medical Research and Development. The investigators disclosed laboratory funding from Terumo for cooperative research in cell sheet.
For patients with ischemic cardiomyopathy (ICM), transplanting sheets of autologous myoblasts onto the epicardial surface was safe and led to “marked” improvements in functional and laboratory measures, investigators reported.
However, cell sheet transplantation was much less effective for patients with dilated cardiomyopathy in this phase I trial, wrote Shigeru Miyagawa, MD, PhD, of Osaka (Japan) University, and his associates in the Journal of the American Heart Association. The findings merit additional follow-up in larger clinical studies, the investigators asserted.
Heart failure remains life threatening even with the best approved treatments. Previously, the researchers transplanted scaffold-free sheets of autologous myoblasts derived from skeletal muscle into small and large animals with heart failure and found that this approach healed severely damaged myocardium. Transplantation caused secreted cytokines to induce native regeneration through paracrine effects, Dr. Miyagawa noted in a prior review article (BioMed Research International. 2013. doi: 10.1155/2013/583912).
To evaluate this approach in humans, the researchers transplanted 15 patients with ischemic cardiomyopathy and 12 patients with dilated cardiomyopathy (DCM). Patients were 20-75 years old, had ejection fractions under 35% and New York Heart Association (NYHA) classifications of II or more, and were responding inadequately to standard treatment with a beta-blocker or ACE inhibitor and an angiotensin receptor blocker. The sole intervention was transplantation of the cell sheet over the left ventricular-free wall during left thoracotomy (J Am Heart Assoc. 2017 Apr 5. doi: 10.1161/JAHA.116.003918). There were no major procedure-related complications during follow-up, the researchers said. For patients with ICM, NYHA classifications dropped significantly at 6 months, from 2.9 at baseline to 2.1 at 6 months and 1.9 at 1 year. Six-Minute Walk Test scores improved significantly, from 416 m at baseline to 475 m at 6 months to 484 m at 1 year. Transplantation also led to significant drops in serum brain natriuretic peptide levels (baseline average, 308 pg/mL; 6 months, 191 pg/mL; 1 year, 182 pg/mL). Additionally, ICM patients improved significantly on measures of pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary vein resistance, and left ventricular wall stress.
In contrast, DCM patients did not significantly improve based on the 6-Minute Walk Test, NYHA classification, or brain natriuretic peptide serum levels. Of 12, 3 progressed to NYHA functional class IV by 1-year follow-up and there were five cardiac deaths. There were no cardiac deaths in the ICM group. “It has been reported that regeneration mechanisms in cell sheet mainly depend on angiogenesis induced by secreted cytokines, so cell-sheet implantation may be more suitable for ICM patients, compared with DCM patients, considering pathophysiological aspects,” the researchers wrote.
The study was funded by grants from Regenerative Medicine for Clinical Application, Health and Labor Sciences Research, and the Japan Agency for Medical Research and Development. The investigators disclosed laboratory funding from Terumo for cooperative research in cell sheet.
Key clinical point: Transplanting a sheet of autologous myoblasts onto the epicardial surface was safe and was associated with functional and symptomatic improvements in patients with ischemic cardiomyopathy.
Major finding: Patients improved significantly on the 6-Minute Walk Test, New York Heart Classification, and on measures of brain natriuretic peptide, pulmonary artery pressure, pulmonary capillary wedge pressure, pulmonary vein resistance, and left ventricular wall stress. These effects did not extend to patients with dilated cardiomyopathy.
Data source: A phase I trial of 27 patients with ischemic or dilated cardiomyopathy.
Disclosures: The study was funded by grants from Regenerative Medicine for Clinical Application, Health and Labor Sciences Research, and the Japan Agency for Medical Research and Development. The investigators disclosed laboratory funding from Terumo for cooperative research in cell sheet.
Off-the-shelf T cells an option for post-HCT viral infections
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.
“Traditionally, we have generated T cells for infusion from the stem cell donor” by isolating and then stimulating and expanding the peripheral blood mononuclear cells for about 10 days ex vivo, said Dr. Tzannou. At that point, the clonal multivirus-resistant T cells can then be transferred to the recipient.
Donor-derived T cells have been used to prevent and treat Epstein-Barr virus (EBV), cytomegalovirus (CMV), adenovirus (AdV), BK virus (BKV), and human herpes virus 6 (HHV6) infections. The approach has been safe, reconstituting antiviral immunity and clearing disease effectively, with a 94% response rate reported in one recent study. However, said Dr. Tzannou, donor-derived virus-specific T cells (VSTs) have their limitations. Donors are increasingly younger and cord blood is being used more commonly, so there are growing numbers of donors who are seronegative for pathogenic viruses. In addition, the 10 days of production time and the additional week or 10 days required for release means that donor-derived VSTs can’t be urgently used.
The concept of banked third party VST therapy came about to address those limitations, said Dr. Tzannou of Baylor College of Medicine, Houston.
In a banked VST scenario, donor T cells with specific multiviral immunity are human leukocyte antigen (HLA) typed, expanded, and cryopreserved. A post-HCT patient with drug-refractory viral illness can receive T cells that are partially matched at HLA –A, HLA-B, or HLA-DR. Dr. Tzannou said that her group has now generated a bank of 59 VST lines to use in clinical testing of the third party approach.
In the study, Dr. Tzannou and her colleagues included both pediatric and adult post-allo-HCT patients with refractory EBV, CMV, AdV, BKV, and/or HHV6 infections. All had either failed a 14-day trial of antiviral therapy or could not tolerate antivirals. Patients could not be on more than 0.5 mg/kg per day of prednisone; they had to have an absolute neutrophil count above 500 per microliter and hemoglobin greater than 8 g/dL. Patients were excluded if they had acute GVHD of grade 2 or higher. There had to be a compatible VST line available that matched both the patient’s illness and HLA typing.
Patients initially received 20,000,000 VST cells per square meter of body surface area. If the investigators saw a partial response, patients could receive additional VST doses every 2 weeks.
Of the 42 patients infused, 23 received one infusion and 19 required two or more infusions. Seven study participants had two viral infections; 18 had CMV, 2 had EBV, 9 had AdV, 17 had BKV, and 3 had HHV6.
Dr. Tzannou and her colleagues tracked the virus-specific T cells and viral load for particular viruses. Virus-specific peripheral T cell counts also rose measurably and viral load plummeted within 2 weeks of VST infusions for most patients.
Overall, 93% of patients met the primary outcome measure of achieving complete or partial response; a partial response was defined as a 50% or better decrease in the viral load and/or clinical improvement.
All of the 17 BKV patients treated to date had tissue disease; 15 had hemorrhagic cystitis and 2 had nephritis. All responded to VSTs, and all of those with hemorrhagic cystitis had symptomatic improvement or resolution.
Overall, the safety profile for VST was good, said Dr. Tzannou. Four patients developed grade 1 acute cutaneous GVHD within 45 days of infusion; one of these developed de novo, but resolved with topical steroids. Another patient had a flare of gastrointestinal GVHD when immunosuppresion was being tapered. One more patient had a transient fever post infusion that resolved spontaneously, said Dr. Tzannou.
Next steps include a multicenter registration study, said Dr. Tzannou, who reports being a consultant for ViraCyte, which helped fund the study.
[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.
“Traditionally, we have generated T cells for infusion from the stem cell donor” by isolating and then stimulating and expanding the peripheral blood mononuclear cells for about 10 days ex vivo, said Dr. Tzannou. At that point, the clonal multivirus-resistant T cells can then be transferred to the recipient.
Donor-derived T cells have been used to prevent and treat Epstein-Barr virus (EBV), cytomegalovirus (CMV), adenovirus (AdV), BK virus (BKV), and human herpes virus 6 (HHV6) infections. The approach has been safe, reconstituting antiviral immunity and clearing disease effectively, with a 94% response rate reported in one recent study. However, said Dr. Tzannou, donor-derived virus-specific T cells (VSTs) have their limitations. Donors are increasingly younger and cord blood is being used more commonly, so there are growing numbers of donors who are seronegative for pathogenic viruses. In addition, the 10 days of production time and the additional week or 10 days required for release means that donor-derived VSTs can’t be urgently used.
The concept of banked third party VST therapy came about to address those limitations, said Dr. Tzannou of Baylor College of Medicine, Houston.
In a banked VST scenario, donor T cells with specific multiviral immunity are human leukocyte antigen (HLA) typed, expanded, and cryopreserved. A post-HCT patient with drug-refractory viral illness can receive T cells that are partially matched at HLA –A, HLA-B, or HLA-DR. Dr. Tzannou said that her group has now generated a bank of 59 VST lines to use in clinical testing of the third party approach.
In the study, Dr. Tzannou and her colleagues included both pediatric and adult post-allo-HCT patients with refractory EBV, CMV, AdV, BKV, and/or HHV6 infections. All had either failed a 14-day trial of antiviral therapy or could not tolerate antivirals. Patients could not be on more than 0.5 mg/kg per day of prednisone; they had to have an absolute neutrophil count above 500 per microliter and hemoglobin greater than 8 g/dL. Patients were excluded if they had acute GVHD of grade 2 or higher. There had to be a compatible VST line available that matched both the patient’s illness and HLA typing.
Patients initially received 20,000,000 VST cells per square meter of body surface area. If the investigators saw a partial response, patients could receive additional VST doses every 2 weeks.
Of the 42 patients infused, 23 received one infusion and 19 required two or more infusions. Seven study participants had two viral infections; 18 had CMV, 2 had EBV, 9 had AdV, 17 had BKV, and 3 had HHV6.
Dr. Tzannou and her colleagues tracked the virus-specific T cells and viral load for particular viruses. Virus-specific peripheral T cell counts also rose measurably and viral load plummeted within 2 weeks of VST infusions for most patients.
Overall, 93% of patients met the primary outcome measure of achieving complete or partial response; a partial response was defined as a 50% or better decrease in the viral load and/or clinical improvement.
All of the 17 BKV patients treated to date had tissue disease; 15 had hemorrhagic cystitis and 2 had nephritis. All responded to VSTs, and all of those with hemorrhagic cystitis had symptomatic improvement or resolution.
Overall, the safety profile for VST was good, said Dr. Tzannou. Four patients developed grade 1 acute cutaneous GVHD within 45 days of infusion; one of these developed de novo, but resolved with topical steroids. Another patient had a flare of gastrointestinal GVHD when immunosuppresion was being tapered. One more patient had a transient fever post infusion that resolved spontaneously, said Dr. Tzannou.
Next steps include a multicenter registration study, said Dr. Tzannou, who reports being a consultant for ViraCyte, which helped fund the study.
[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.
“Traditionally, we have generated T cells for infusion from the stem cell donor” by isolating and then stimulating and expanding the peripheral blood mononuclear cells for about 10 days ex vivo, said Dr. Tzannou. At that point, the clonal multivirus-resistant T cells can then be transferred to the recipient.
Donor-derived T cells have been used to prevent and treat Epstein-Barr virus (EBV), cytomegalovirus (CMV), adenovirus (AdV), BK virus (BKV), and human herpes virus 6 (HHV6) infections. The approach has been safe, reconstituting antiviral immunity and clearing disease effectively, with a 94% response rate reported in one recent study. However, said Dr. Tzannou, donor-derived virus-specific T cells (VSTs) have their limitations. Donors are increasingly younger and cord blood is being used more commonly, so there are growing numbers of donors who are seronegative for pathogenic viruses. In addition, the 10 days of production time and the additional week or 10 days required for release means that donor-derived VSTs can’t be urgently used.
The concept of banked third party VST therapy came about to address those limitations, said Dr. Tzannou of Baylor College of Medicine, Houston.
In a banked VST scenario, donor T cells with specific multiviral immunity are human leukocyte antigen (HLA) typed, expanded, and cryopreserved. A post-HCT patient with drug-refractory viral illness can receive T cells that are partially matched at HLA –A, HLA-B, or HLA-DR. Dr. Tzannou said that her group has now generated a bank of 59 VST lines to use in clinical testing of the third party approach.
In the study, Dr. Tzannou and her colleagues included both pediatric and adult post-allo-HCT patients with refractory EBV, CMV, AdV, BKV, and/or HHV6 infections. All had either failed a 14-day trial of antiviral therapy or could not tolerate antivirals. Patients could not be on more than 0.5 mg/kg per day of prednisone; they had to have an absolute neutrophil count above 500 per microliter and hemoglobin greater than 8 g/dL. Patients were excluded if they had acute GVHD of grade 2 or higher. There had to be a compatible VST line available that matched both the patient’s illness and HLA typing.
Patients initially received 20,000,000 VST cells per square meter of body surface area. If the investigators saw a partial response, patients could receive additional VST doses every 2 weeks.
Of the 42 patients infused, 23 received one infusion and 19 required two or more infusions. Seven study participants had two viral infections; 18 had CMV, 2 had EBV, 9 had AdV, 17 had BKV, and 3 had HHV6.
Dr. Tzannou and her colleagues tracked the virus-specific T cells and viral load for particular viruses. Virus-specific peripheral T cell counts also rose measurably and viral load plummeted within 2 weeks of VST infusions for most patients.
Overall, 93% of patients met the primary outcome measure of achieving complete or partial response; a partial response was defined as a 50% or better decrease in the viral load and/or clinical improvement.
All of the 17 BKV patients treated to date had tissue disease; 15 had hemorrhagic cystitis and 2 had nephritis. All responded to VSTs, and all of those with hemorrhagic cystitis had symptomatic improvement or resolution.
Overall, the safety profile for VST was good, said Dr. Tzannou. Four patients developed grade 1 acute cutaneous GVHD within 45 days of infusion; one of these developed de novo, but resolved with topical steroids. Another patient had a flare of gastrointestinal GVHD when immunosuppresion was being tapered. One more patient had a transient fever post infusion that resolved spontaneously, said Dr. Tzannou.
Next steps include a multicenter registration study, said Dr. Tzannou, who reports being a consultant for ViraCyte, which helped fund the study.
[email protected]
On Twitter @karioakes
AT THE 2017 BMT TANDEM MEETINGS
Key clinical point:
Major finding: With banked multivirus-specific T cells, viral illnesses either improved or resolved in 93% of 42 patients.
Data source: Clinical trial of 42 postallogeneic hematopoietic cell transfer patients who had any of five viral illnesses and had either failed a 14-day trial of antiviral therapy or could not tolerate antivirals.
Disclosures: Dr. Tzannou is a consultant for Incyte, which partially funded the trial and is developing third-party VSTs.
Tocilizumab shows promise for GVHD prevention
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.
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.
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.
Key clinical point:
Major finding: The probability of grade II-IV acute GVHD-free survival was 79% vs. 52% in the tocilizumab group vs. age-matched controls.
Data source: An open-label phase II study of 35 patients.
Disclosures: Dr. Drobyski reported having no disclosures.
CAR designers report high B-cell cancer response rates
ORLANDO – Patients with advanced hematologic malignancies of B-cell lineage had robust immune responses following infusion of a chimeric antigen receptor (CAR)–T-cell construct designed to deliver a specific balance of antigens, investigators reported.
Adults with relapsed or refractory B-lineage acute myeloid leukemia (ALL), non–Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL) who received a CAR-T cell construct consisting of autologous CD4-positive and CD-8-positive T cells that were transduced separately, recombined, and then delivered in a single infusion had comparatively high overall response and complete response rates, reported Cameron Turtle, MBBS, PhD, from the Fred Hutchinson Cancer Research Center in Seattle.
“We know that patients have a highly variable CD4 to CD8 ratio, so by actually controlling this and separately transducing, expanding, and then reformulating in this defined composition, we’re able to eliminate one source of variability in CAR-T cell products,” Dr. Turtle said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
In preclinical studies, an even balance of CD4-positive and CD8-positive central memory T cells or naive T cells evoked more potent immune responses against B-cell malignancies in mice than CD19-positive cells, he explained
To see whether this would also hold true in humans, the investigators enrolled into a phase I/II trial adults with relapsed/refractory B-cell malignancies, including ALL (36 patients), NHL (41), and CLL (24). No patients were excluded on the basis of either absolute lymphocyte, circulating tumors cells, history of stem cell transplant, or results of in vitro test expansions.
All patients underwent leukapheresis for harvesting of T-cells, and populations of CD4- and CD8-positive cells were separated and transduced with a lentiviral vector to express a CD19 CAR and a truncated human epidermal growth factor receptor that allowed tracing of the transduced cells via flow cytometry. The patients underwent lymphodepleting chemotherapy with cyclophosphamide (for the earliest patients), or cyclophosphamide plus fludarabine. Fifteen days after leukapheresis, the separated, transduced, and expanded cells were combined and delivered back to patients in a single infusion at one of three dose levels: 2 x 105, 2 x 106, or 2 x 107 CAR-T cells/kg.
ALL results
Two of the 36 patients with ALL died from complications of the CAR-T cell infusion process prior to evaluation. The 34 remaining patients all had morphologic bone marrow complete responses (CR). Of this group, 32 also had bone marrow CR on flow cytometry.
Using immunoglobulin H (IgH) deep sequencing in a subset of 20 patients 3 weeks after CAR-T cell infusion, the investigators could not detect the malignant IgH index clone in 13 of the patients, and found fewer than 10 copies in the bone marrow of 5 patients.
Six of seven patients with extramedullary disease at baseline had a complete response. The remaining patient in this group had an equivocal PET scan result, and experienced a relapse 2 months after assessment.
The investigators also determined that the lymphodepletion regimen may affect overall results, based on the finding that 10 of 12 patients who received cyclophosphamide alone achieved a CR, but seven of these 10 patients had a relapse within a few months. Of these seven patients. five received a second T-cell infusion, but none had significant T-cell expansion. The investigators traced the failure of the second attempt to a CD8-mediated transgene immune response to a murine single-chain variable fragment used in the construct.
For subsequent patients, they altered the lymphodepletion regimen to include fludarabine to prevent priming of the anti-CAR transgenic immune response. This modification resulted in improved progression-free survival and overall survival for subsequent patients receiving a second infusion, Dr. Turtle said.
NHL results
Of the 41 patients with NHL, 30 (73%) had aggressive histologies, including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell, and Burkitt lymphomas, and 11 (27%) had indolent histologies, including mantle cell and follicular lymphomas. Most of the patients had received multiple prior lines of therapy, and 19 (46%) had undergone either an autologous or allogeneic stem cell transplant.
Of the 39 evaluable patients who completed therapy, the overall response rate was 67%, including 13 (39%) with CR. Dr. Turtle noted that the CR rate was substantially higher among patients who received cyclophosphamide and fludarabine lymphodepletion, compared with cyclophosphamide alone.
There were also a few responses, including two CRs, among patients with indolent histologies, he said.
CLL, safety results
All 24 patients with CLL had previously received ibrutinib (Imbruvica). Of this group, 19 either had no significant responses to the drug, inactivating mutations, or intolerable toxicities. All but 1 of the 24 patients also had high-risk cytogenetics.
Of the 16 ibrutinib-refractory patients who were evaluable for restaging, 14 had no evidence of disease in bone marrow by flow cytometry at 4 weeks. The overall response rate in this group was 69%, which included four CRs.
Among a majority of all patients, toxicity with the CAR-T cell therapy was mild to moderate. Early cytokine changes appeared to be predictive of serious adverse events such as the cytokine release syndrome, a finding that may allow clinicians to intervene early to prevent complications, Dr. Turtle said.
In the CAR-T cell therapy, “multiple things affect the response and toxicity, including CAR T-cell dose, disease burden, the anti-CAR transgene immune response and the lymphodepletion regimen, not to mention other patient factors that we’re still sorting out,” he commented.
The trial was funded by the National Institutes of Health, Life Science Development Fund, Juno Therapeutics and the Bezos Family Foundation. Dr. Turtle disclosed consultancy, honoraria, and/or research funding from Juno Therapeutics and Seattle Genetics.
ORLANDO – Patients with advanced hematologic malignancies of B-cell lineage had robust immune responses following infusion of a chimeric antigen receptor (CAR)–T-cell construct designed to deliver a specific balance of antigens, investigators reported.
Adults with relapsed or refractory B-lineage acute myeloid leukemia (ALL), non–Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL) who received a CAR-T cell construct consisting of autologous CD4-positive and CD-8-positive T cells that were transduced separately, recombined, and then delivered in a single infusion had comparatively high overall response and complete response rates, reported Cameron Turtle, MBBS, PhD, from the Fred Hutchinson Cancer Research Center in Seattle.
“We know that patients have a highly variable CD4 to CD8 ratio, so by actually controlling this and separately transducing, expanding, and then reformulating in this defined composition, we’re able to eliminate one source of variability in CAR-T cell products,” Dr. Turtle said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
In preclinical studies, an even balance of CD4-positive and CD8-positive central memory T cells or naive T cells evoked more potent immune responses against B-cell malignancies in mice than CD19-positive cells, he explained
To see whether this would also hold true in humans, the investigators enrolled into a phase I/II trial adults with relapsed/refractory B-cell malignancies, including ALL (36 patients), NHL (41), and CLL (24). No patients were excluded on the basis of either absolute lymphocyte, circulating tumors cells, history of stem cell transplant, or results of in vitro test expansions.
All patients underwent leukapheresis for harvesting of T-cells, and populations of CD4- and CD8-positive cells were separated and transduced with a lentiviral vector to express a CD19 CAR and a truncated human epidermal growth factor receptor that allowed tracing of the transduced cells via flow cytometry. The patients underwent lymphodepleting chemotherapy with cyclophosphamide (for the earliest patients), or cyclophosphamide plus fludarabine. Fifteen days after leukapheresis, the separated, transduced, and expanded cells were combined and delivered back to patients in a single infusion at one of three dose levels: 2 x 105, 2 x 106, or 2 x 107 CAR-T cells/kg.
ALL results
Two of the 36 patients with ALL died from complications of the CAR-T cell infusion process prior to evaluation. The 34 remaining patients all had morphologic bone marrow complete responses (CR). Of this group, 32 also had bone marrow CR on flow cytometry.
Using immunoglobulin H (IgH) deep sequencing in a subset of 20 patients 3 weeks after CAR-T cell infusion, the investigators could not detect the malignant IgH index clone in 13 of the patients, and found fewer than 10 copies in the bone marrow of 5 patients.
Six of seven patients with extramedullary disease at baseline had a complete response. The remaining patient in this group had an equivocal PET scan result, and experienced a relapse 2 months after assessment.
The investigators also determined that the lymphodepletion regimen may affect overall results, based on the finding that 10 of 12 patients who received cyclophosphamide alone achieved a CR, but seven of these 10 patients had a relapse within a few months. Of these seven patients. five received a second T-cell infusion, but none had significant T-cell expansion. The investigators traced the failure of the second attempt to a CD8-mediated transgene immune response to a murine single-chain variable fragment used in the construct.
For subsequent patients, they altered the lymphodepletion regimen to include fludarabine to prevent priming of the anti-CAR transgenic immune response. This modification resulted in improved progression-free survival and overall survival for subsequent patients receiving a second infusion, Dr. Turtle said.
NHL results
Of the 41 patients with NHL, 30 (73%) had aggressive histologies, including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell, and Burkitt lymphomas, and 11 (27%) had indolent histologies, including mantle cell and follicular lymphomas. Most of the patients had received multiple prior lines of therapy, and 19 (46%) had undergone either an autologous or allogeneic stem cell transplant.
Of the 39 evaluable patients who completed therapy, the overall response rate was 67%, including 13 (39%) with CR. Dr. Turtle noted that the CR rate was substantially higher among patients who received cyclophosphamide and fludarabine lymphodepletion, compared with cyclophosphamide alone.
There were also a few responses, including two CRs, among patients with indolent histologies, he said.
CLL, safety results
All 24 patients with CLL had previously received ibrutinib (Imbruvica). Of this group, 19 either had no significant responses to the drug, inactivating mutations, or intolerable toxicities. All but 1 of the 24 patients also had high-risk cytogenetics.
Of the 16 ibrutinib-refractory patients who were evaluable for restaging, 14 had no evidence of disease in bone marrow by flow cytometry at 4 weeks. The overall response rate in this group was 69%, which included four CRs.
Among a majority of all patients, toxicity with the CAR-T cell therapy was mild to moderate. Early cytokine changes appeared to be predictive of serious adverse events such as the cytokine release syndrome, a finding that may allow clinicians to intervene early to prevent complications, Dr. Turtle said.
In the CAR-T cell therapy, “multiple things affect the response and toxicity, including CAR T-cell dose, disease burden, the anti-CAR transgene immune response and the lymphodepletion regimen, not to mention other patient factors that we’re still sorting out,” he commented.
The trial was funded by the National Institutes of Health, Life Science Development Fund, Juno Therapeutics and the Bezos Family Foundation. Dr. Turtle disclosed consultancy, honoraria, and/or research funding from Juno Therapeutics and Seattle Genetics.
ORLANDO – Patients with advanced hematologic malignancies of B-cell lineage had robust immune responses following infusion of a chimeric antigen receptor (CAR)–T-cell construct designed to deliver a specific balance of antigens, investigators reported.
Adults with relapsed or refractory B-lineage acute myeloid leukemia (ALL), non–Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL) who received a CAR-T cell construct consisting of autologous CD4-positive and CD-8-positive T cells that were transduced separately, recombined, and then delivered in a single infusion had comparatively high overall response and complete response rates, reported Cameron Turtle, MBBS, PhD, from the Fred Hutchinson Cancer Research Center in Seattle.
“We know that patients have a highly variable CD4 to CD8 ratio, so by actually controlling this and separately transducing, expanding, and then reformulating in this defined composition, we’re able to eliminate one source of variability in CAR-T cell products,” Dr. Turtle said at the ASCO-SITC Clinical Immuno-Oncology Symposium.
In preclinical studies, an even balance of CD4-positive and CD8-positive central memory T cells or naive T cells evoked more potent immune responses against B-cell malignancies in mice than CD19-positive cells, he explained
To see whether this would also hold true in humans, the investigators enrolled into a phase I/II trial adults with relapsed/refractory B-cell malignancies, including ALL (36 patients), NHL (41), and CLL (24). No patients were excluded on the basis of either absolute lymphocyte, circulating tumors cells, history of stem cell transplant, or results of in vitro test expansions.
All patients underwent leukapheresis for harvesting of T-cells, and populations of CD4- and CD8-positive cells were separated and transduced with a lentiviral vector to express a CD19 CAR and a truncated human epidermal growth factor receptor that allowed tracing of the transduced cells via flow cytometry. The patients underwent lymphodepleting chemotherapy with cyclophosphamide (for the earliest patients), or cyclophosphamide plus fludarabine. Fifteen days after leukapheresis, the separated, transduced, and expanded cells were combined and delivered back to patients in a single infusion at one of three dose levels: 2 x 105, 2 x 106, or 2 x 107 CAR-T cells/kg.
ALL results
Two of the 36 patients with ALL died from complications of the CAR-T cell infusion process prior to evaluation. The 34 remaining patients all had morphologic bone marrow complete responses (CR). Of this group, 32 also had bone marrow CR on flow cytometry.
Using immunoglobulin H (IgH) deep sequencing in a subset of 20 patients 3 weeks after CAR-T cell infusion, the investigators could not detect the malignant IgH index clone in 13 of the patients, and found fewer than 10 copies in the bone marrow of 5 patients.
Six of seven patients with extramedullary disease at baseline had a complete response. The remaining patient in this group had an equivocal PET scan result, and experienced a relapse 2 months after assessment.
The investigators also determined that the lymphodepletion regimen may affect overall results, based on the finding that 10 of 12 patients who received cyclophosphamide alone achieved a CR, but seven of these 10 patients had a relapse within a few months. Of these seven patients. five received a second T-cell infusion, but none had significant T-cell expansion. The investigators traced the failure of the second attempt to a CD8-mediated transgene immune response to a murine single-chain variable fragment used in the construct.
For subsequent patients, they altered the lymphodepletion regimen to include fludarabine to prevent priming of the anti-CAR transgenic immune response. This modification resulted in improved progression-free survival and overall survival for subsequent patients receiving a second infusion, Dr. Turtle said.
NHL results
Of the 41 patients with NHL, 30 (73%) had aggressive histologies, including diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell, and Burkitt lymphomas, and 11 (27%) had indolent histologies, including mantle cell and follicular lymphomas. Most of the patients had received multiple prior lines of therapy, and 19 (46%) had undergone either an autologous or allogeneic stem cell transplant.
Of the 39 evaluable patients who completed therapy, the overall response rate was 67%, including 13 (39%) with CR. Dr. Turtle noted that the CR rate was substantially higher among patients who received cyclophosphamide and fludarabine lymphodepletion, compared with cyclophosphamide alone.
There were also a few responses, including two CRs, among patients with indolent histologies, he said.
CLL, safety results
All 24 patients with CLL had previously received ibrutinib (Imbruvica). Of this group, 19 either had no significant responses to the drug, inactivating mutations, or intolerable toxicities. All but 1 of the 24 patients also had high-risk cytogenetics.
Of the 16 ibrutinib-refractory patients who were evaluable for restaging, 14 had no evidence of disease in bone marrow by flow cytometry at 4 weeks. The overall response rate in this group was 69%, which included four CRs.
Among a majority of all patients, toxicity with the CAR-T cell therapy was mild to moderate. Early cytokine changes appeared to be predictive of serious adverse events such as the cytokine release syndrome, a finding that may allow clinicians to intervene early to prevent complications, Dr. Turtle said.
In the CAR-T cell therapy, “multiple things affect the response and toxicity, including CAR T-cell dose, disease burden, the anti-CAR transgene immune response and the lymphodepletion regimen, not to mention other patient factors that we’re still sorting out,” he commented.
The trial was funded by the National Institutes of Health, Life Science Development Fund, Juno Therapeutics and the Bezos Family Foundation. Dr. Turtle disclosed consultancy, honoraria, and/or research funding from Juno Therapeutics and Seattle Genetics.
AT THE CLINICAL IMMUNO-ONCOLOGY SYMPOSIUM
Key clinical point: A defined CAR-T cell construct was associated with high response rates in patients with B-cell malignancies.
Major finding: The overall response rate among patients with ibrutinib-refractory chronic lymphocytic leukemia was 69%, including four complete responses.
Data source: Phase I/II dose-finding, safety and efficacy study in patients with B-lineage hematologic malignancies
Disclosures: The trial was funded by the National Institutes of Health, Life Science Development Fund, Juno Therapeutics and the Bezos Family Foundation. Dr. Turtle disclosed consultancy, honoraria, and/or research funding from Juno Therapeutics and Seattle Genetics.
Adding rituximab to reduced intensity conditioning boosts PFS
ORLANDO – Rituximab conferred a significant progression-free survival benefit in reduced intensity conditioning regimens for patients with B-cell non-Hodgkin lymphoma who underwent allogeneic hematopoietic cell transplantation, based on data from the Center for International Blood & Marrow Transplant Research.
Further, higher cumulative rituximab doses appeared to confer a benefit in overall survival.
Rituximab is frequently a component of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic cell transplantation (HCT), but there has been a “paucity of comparative data” for rituximab-containing (R-RIC) versus non–R-RIC conditioning regimens for allogeneic transplant patients, Narendranath Epperla, MD, of the Medical College of Wisconsin, Milwaukee, said during the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.
Using data from the Center for International Blood & Marrow Transplant Research, Dr. Epperla and his colleagues identified 1,022 patients who received rituximab and 379 patients who did not with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. The patients received their first RIC or non-myeloablative allogeneic HCT between 2008 and 2014. The donors were matched, and either related or 8x8 allele-matched unrelated; the graft source could be bone marrow or peripheral blood. Graft versus host disease (GVHD) suppression was calcineurin inhibitor based.
Patients who had received myeloablative conditioning, or who had received radioimmunotherapy or alemtuzumab were excluded, as were those who received alternative donor allografts.
Dr. Epperla and his colleagues factored in patient and disease characteristics, as well as differences in transplant regimen, in determining the adjusted cumulative incidence of relapse or progression, as well as the incidence of nonrelapse mortality.
In the multivariable analysis, overall survival did not differ between the R-RIC and the non–R-RIC cohorts (relative risk [RR] of all-cause mortality, R-RIC = 0.83, 95% CI 0.67-1.03, P = .09).
Based on the cumulative dose of rituximab that patients had received, though, “we noted that patients who got higher doses of rituximab had lower risk of nonrelapse mortality,” Dr. Epperla said. “Higher cumulative doses of rituximab seem to confer overall survival benefit.” This was true even though the higher rituximab doses had no significant effect on the risk of therapy failure, nonrelapse mortality, or the risk of progression/relapse.
When the cumulative rituximab dose was 2,000 to 3,375 mg/m2, the hazard ratio for all-cause mortality fell to 0.43 compared to a cumulative rituximab dose of less than 1,000 mg/m2 (95% confidence interval [CI] 0.21-0.90, P = .02).
Among the R-RIC group, there was a nonsignificant trend toward reduced risk of progression or relapse (relative risk of progression/relapse, R-RIC = 0.79, 95% CI 0.63-1.01, P = .055). However, the R-RIC group fared significantly better in terms of progression-free survival (RR of PFS, R-RIC = 0.76, 95% CI 0.62-0.92, P = .006).
After transplant, patients in the R-RIC group were no more likely than those in the non–R-RIC group to experience chronic GVHD (RR of GVHD, R-RIC = 1.15, 95% CI 0.96-1.39, P = .13). There was no difference in the adjusted curves of nonrelapse mortality between the groups (RR of nonrelapse mortality, R-RIC = 0.90, 95% CI 0.67-1.22, P = .51).
Also, there were no fatal cytopenias in the R-RIC arm, although the literature warrants some concern for increased risk of infection with rituximab, Dr. Epperla said.
At baseline, there were no significant differences in demographic characteristics between the nonrituximab and rituximab arms of the study population. More than 90% of patients were white, and 65% were male; the median age was 57 years (range, 18-74).
Patients had been diagnosed about 3 years before receiving HCT; about 60% of patients had a baseline Karnofsky performance score greater than 90, and the HCT comorbidity index was 2. About 86% of patients were chemosensitive, and patients in both study arms had received a median of three prior lines of therapy.
There were some differences in conditioning regimens between the two groups. “There were a significantly higher number of patients in the nonrituximab group who received fludarabine/busulfan, while there were a significantly high number in the rituximab group who received a fludarabine/cyclophosphamide-based conditioning regimen,” Dr. Epperla said. Follicular lymphomas were more common in the R-RIC arm, while diffuse large B-cell lymphomas were seen more in the non–R-RIC arm.
Given the survival benefit and similar rates of chronic GVHD seen in the retrospective analysis, a prospective, randomized head-to-head trial of R-RIC versus non–R-RIC is warranted, Dr. Epperla concluded.
During the postpresentation discussion, Dr. Epperla acknowledged the variability of the lymphomas in the study, but that there was no significant statistical effect of specific histologies on the findings in a subgroup analysis. Dr. Epperla added that the chemosensitivity status at transplant was checked to account for patient exposure to rituximab before RIC, and that there was no effect of prior rituximab exposure on the outcomes examined.
Dr. Epperla reported no conflicts of interest.
[email protected]
On Twitter @karioakes
ORLANDO – Rituximab conferred a significant progression-free survival benefit in reduced intensity conditioning regimens for patients with B-cell non-Hodgkin lymphoma who underwent allogeneic hematopoietic cell transplantation, based on data from the Center for International Blood & Marrow Transplant Research.
Further, higher cumulative rituximab doses appeared to confer a benefit in overall survival.
Rituximab is frequently a component of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic cell transplantation (HCT), but there has been a “paucity of comparative data” for rituximab-containing (R-RIC) versus non–R-RIC conditioning regimens for allogeneic transplant patients, Narendranath Epperla, MD, of the Medical College of Wisconsin, Milwaukee, said during the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.
Using data from the Center for International Blood & Marrow Transplant Research, Dr. Epperla and his colleagues identified 1,022 patients who received rituximab and 379 patients who did not with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. The patients received their first RIC or non-myeloablative allogeneic HCT between 2008 and 2014. The donors were matched, and either related or 8x8 allele-matched unrelated; the graft source could be bone marrow or peripheral blood. Graft versus host disease (GVHD) suppression was calcineurin inhibitor based.
Patients who had received myeloablative conditioning, or who had received radioimmunotherapy or alemtuzumab were excluded, as were those who received alternative donor allografts.
Dr. Epperla and his colleagues factored in patient and disease characteristics, as well as differences in transplant regimen, in determining the adjusted cumulative incidence of relapse or progression, as well as the incidence of nonrelapse mortality.
In the multivariable analysis, overall survival did not differ between the R-RIC and the non–R-RIC cohorts (relative risk [RR] of all-cause mortality, R-RIC = 0.83, 95% CI 0.67-1.03, P = .09).
Based on the cumulative dose of rituximab that patients had received, though, “we noted that patients who got higher doses of rituximab had lower risk of nonrelapse mortality,” Dr. Epperla said. “Higher cumulative doses of rituximab seem to confer overall survival benefit.” This was true even though the higher rituximab doses had no significant effect on the risk of therapy failure, nonrelapse mortality, or the risk of progression/relapse.
When the cumulative rituximab dose was 2,000 to 3,375 mg/m2, the hazard ratio for all-cause mortality fell to 0.43 compared to a cumulative rituximab dose of less than 1,000 mg/m2 (95% confidence interval [CI] 0.21-0.90, P = .02).
Among the R-RIC group, there was a nonsignificant trend toward reduced risk of progression or relapse (relative risk of progression/relapse, R-RIC = 0.79, 95% CI 0.63-1.01, P = .055). However, the R-RIC group fared significantly better in terms of progression-free survival (RR of PFS, R-RIC = 0.76, 95% CI 0.62-0.92, P = .006).
After transplant, patients in the R-RIC group were no more likely than those in the non–R-RIC group to experience chronic GVHD (RR of GVHD, R-RIC = 1.15, 95% CI 0.96-1.39, P = .13). There was no difference in the adjusted curves of nonrelapse mortality between the groups (RR of nonrelapse mortality, R-RIC = 0.90, 95% CI 0.67-1.22, P = .51).
Also, there were no fatal cytopenias in the R-RIC arm, although the literature warrants some concern for increased risk of infection with rituximab, Dr. Epperla said.
At baseline, there were no significant differences in demographic characteristics between the nonrituximab and rituximab arms of the study population. More than 90% of patients were white, and 65% were male; the median age was 57 years (range, 18-74).
Patients had been diagnosed about 3 years before receiving HCT; about 60% of patients had a baseline Karnofsky performance score greater than 90, and the HCT comorbidity index was 2. About 86% of patients were chemosensitive, and patients in both study arms had received a median of three prior lines of therapy.
There were some differences in conditioning regimens between the two groups. “There were a significantly higher number of patients in the nonrituximab group who received fludarabine/busulfan, while there were a significantly high number in the rituximab group who received a fludarabine/cyclophosphamide-based conditioning regimen,” Dr. Epperla said. Follicular lymphomas were more common in the R-RIC arm, while diffuse large B-cell lymphomas were seen more in the non–R-RIC arm.
Given the survival benefit and similar rates of chronic GVHD seen in the retrospective analysis, a prospective, randomized head-to-head trial of R-RIC versus non–R-RIC is warranted, Dr. Epperla concluded.
During the postpresentation discussion, Dr. Epperla acknowledged the variability of the lymphomas in the study, but that there was no significant statistical effect of specific histologies on the findings in a subgroup analysis. Dr. Epperla added that the chemosensitivity status at transplant was checked to account for patient exposure to rituximab before RIC, and that there was no effect of prior rituximab exposure on the outcomes examined.
Dr. Epperla reported no conflicts of interest.
[email protected]
On Twitter @karioakes
ORLANDO – Rituximab conferred a significant progression-free survival benefit in reduced intensity conditioning regimens for patients with B-cell non-Hodgkin lymphoma who underwent allogeneic hematopoietic cell transplantation, based on data from the Center for International Blood & Marrow Transplant Research.
Further, higher cumulative rituximab doses appeared to confer a benefit in overall survival.
Rituximab is frequently a component of reduced intensity conditioning (RIC) regimens in allogeneic hematopoietic cell transplantation (HCT), but there has been a “paucity of comparative data” for rituximab-containing (R-RIC) versus non–R-RIC conditioning regimens for allogeneic transplant patients, Narendranath Epperla, MD, of the Medical College of Wisconsin, Milwaukee, said during the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society of Blood and Marrow Transplantation.
Using data from the Center for International Blood & Marrow Transplant Research, Dr. Epperla and his colleagues identified 1,022 patients who received rituximab and 379 patients who did not with diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and marginal zone lymphoma. The patients received their first RIC or non-myeloablative allogeneic HCT between 2008 and 2014. The donors were matched, and either related or 8x8 allele-matched unrelated; the graft source could be bone marrow or peripheral blood. Graft versus host disease (GVHD) suppression was calcineurin inhibitor based.
Patients who had received myeloablative conditioning, or who had received radioimmunotherapy or alemtuzumab were excluded, as were those who received alternative donor allografts.
Dr. Epperla and his colleagues factored in patient and disease characteristics, as well as differences in transplant regimen, in determining the adjusted cumulative incidence of relapse or progression, as well as the incidence of nonrelapse mortality.
In the multivariable analysis, overall survival did not differ between the R-RIC and the non–R-RIC cohorts (relative risk [RR] of all-cause mortality, R-RIC = 0.83, 95% CI 0.67-1.03, P = .09).
Based on the cumulative dose of rituximab that patients had received, though, “we noted that patients who got higher doses of rituximab had lower risk of nonrelapse mortality,” Dr. Epperla said. “Higher cumulative doses of rituximab seem to confer overall survival benefit.” This was true even though the higher rituximab doses had no significant effect on the risk of therapy failure, nonrelapse mortality, or the risk of progression/relapse.
When the cumulative rituximab dose was 2,000 to 3,375 mg/m2, the hazard ratio for all-cause mortality fell to 0.43 compared to a cumulative rituximab dose of less than 1,000 mg/m2 (95% confidence interval [CI] 0.21-0.90, P = .02).
Among the R-RIC group, there was a nonsignificant trend toward reduced risk of progression or relapse (relative risk of progression/relapse, R-RIC = 0.79, 95% CI 0.63-1.01, P = .055). However, the R-RIC group fared significantly better in terms of progression-free survival (RR of PFS, R-RIC = 0.76, 95% CI 0.62-0.92, P = .006).
After transplant, patients in the R-RIC group were no more likely than those in the non–R-RIC group to experience chronic GVHD (RR of GVHD, R-RIC = 1.15, 95% CI 0.96-1.39, P = .13). There was no difference in the adjusted curves of nonrelapse mortality between the groups (RR of nonrelapse mortality, R-RIC = 0.90, 95% CI 0.67-1.22, P = .51).
Also, there were no fatal cytopenias in the R-RIC arm, although the literature warrants some concern for increased risk of infection with rituximab, Dr. Epperla said.
At baseline, there were no significant differences in demographic characteristics between the nonrituximab and rituximab arms of the study population. More than 90% of patients were white, and 65% were male; the median age was 57 years (range, 18-74).
Patients had been diagnosed about 3 years before receiving HCT; about 60% of patients had a baseline Karnofsky performance score greater than 90, and the HCT comorbidity index was 2. About 86% of patients were chemosensitive, and patients in both study arms had received a median of three prior lines of therapy.
There were some differences in conditioning regimens between the two groups. “There were a significantly higher number of patients in the nonrituximab group who received fludarabine/busulfan, while there were a significantly high number in the rituximab group who received a fludarabine/cyclophosphamide-based conditioning regimen,” Dr. Epperla said. Follicular lymphomas were more common in the R-RIC arm, while diffuse large B-cell lymphomas were seen more in the non–R-RIC arm.
Given the survival benefit and similar rates of chronic GVHD seen in the retrospective analysis, a prospective, randomized head-to-head trial of R-RIC versus non–R-RIC is warranted, Dr. Epperla concluded.
During the postpresentation discussion, Dr. Epperla acknowledged the variability of the lymphomas in the study, but that there was no significant statistical effect of specific histologies on the findings in a subgroup analysis. Dr. Epperla added that the chemosensitivity status at transplant was checked to account for patient exposure to rituximab before RIC, and that there was no effect of prior rituximab exposure on the outcomes examined.
Dr. Epperla reported no conflicts of interest.
[email protected]
On Twitter @karioakes
Key clinical point:
Major finding: Patients with rituximab-containing RIC regimens had better progression-free survival (PFS; relative risk of PFS, non–R-RIC=1, R-RIC=076, 95% CI 0.62-092, P = .006).
Data source: Retrospective review of 1,022 allogeneic HCT B-cell non-Hodgkin lymphoma patients who received rituximab and 379 who did not.
Disclosures: The data were obtained from the Center for International Blood & Marrow Transplant Research. Dr. Epperla reported no disclosures.
Follistatin, endoglin predict postallogeneic HCT NRM
ORLANDO – A composite score based on day 28 plasma levels of the angiogenic factors follistatin and endoglin predicts 1-year nonrelapse mortality in patients who have undergone myeloablative allogeneic hematopoietic cell transplantation, based on findings from the randomized Blood and Marrow Transplant Clinical Trials Network acute graft-versus-host prophylaxis study 0402 (BMT CTN 0402).
Elevations in these factors at day 28 may reflect susceptibility to regimen-related and other toxicities that adversely affect tissue repair and survival, Shernan Holtan, 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.
“Without important trophic angiogenic factors, the body may not be able to heal well after injury such as graft-versus-host disease [GVHD]. We previously reported that such angiogenic factors are indeed altered at the onset of acute graft-versus-host disease based upon samples from BMT CTN 0302 and 0802,” said Dr. Holtan of the University of Minnesota, Minneapolis. “Specifically, we found that repair factors of epidermal growth factor and VEGF-A are low at the onset of acute GVHD, and that damage-associated angiogenic factors are high at the onset of acute graft-versus-host disease.”
These damage-associated factors include follistatin, endoglin, placental growth factor, and angiopoietin-2, she added.
Based on the previous results, Dr. Holtan and her colleagues hypothesized that a pattern of tissue damage as illustrated by these markers at 28 days after treatment would be associated with 1-year nonrelapse mortality.
Of 221 patients from BMT CTN 0402 with pretreatment and day 28 plasma samples available for analysis, 25 had died at 1 year of causes unrelated to relapse. In a univariate analysis, nonrelapse mortality was associated with levels of follistatin, endoglin, and angiopoietin-2. When combined to assess for an overall pattern of damage, only follistatin and endoglin were significantly associated with nonrelapse mortality.
The relative risk of death unrelated to relapse was 4.5-fold higher in patients with the highest score (score of 3) on multivariate regression analysis of follistatin and endoglin levels. Grade II-IV acute GVHD was not significantly associated with 1-year nonrelapse mortality in multivariate analyses, but age over 50 years was.
“Notably, the composite score was a better predictor than any factor alone,” Dr. Holtan said.
The composite score was also predictive of the development of acute GVHD.
“We found that a moderate score of 2 was associated with a 2.3-fold increased risk of acute GVHD prior to day 100. Interestingly, the higher score [3] was not associated with acute GVHD. There was no association of the composite score with chronic GVHD,” she said.
The risk of nonrelapse mortality was less than 10% in patients with a composite score of 1.
Among patients in the study with a score of 3, more than half of the deaths were related to organ toxicity, including liver failure and respiratory failure, which were predominantly infection-related. Those with a low composite score had very few deaths associated with organ toxicity, she noted.
While there are many unanswered questions, these findings highlight possible opportunities to improve survival after allogeneic hematopoietic cell transplantation that warrant further study, she said.
“We need to learn how to constrain this angiogenic inflammatory response with the ultimate goal of hopefully identifying novel treatment strategies to mitigate nonrelapse mortality in our patients,” she concluded.
Dr. Holtan is an investigator for Alexion and is site principal investigator on the GI GVHD clinical trial.
ORLANDO – A composite score based on day 28 plasma levels of the angiogenic factors follistatin and endoglin predicts 1-year nonrelapse mortality in patients who have undergone myeloablative allogeneic hematopoietic cell transplantation, based on findings from the randomized Blood and Marrow Transplant Clinical Trials Network acute graft-versus-host prophylaxis study 0402 (BMT CTN 0402).
Elevations in these factors at day 28 may reflect susceptibility to regimen-related and other toxicities that adversely affect tissue repair and survival, Shernan Holtan, 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.
“Without important trophic angiogenic factors, the body may not be able to heal well after injury such as graft-versus-host disease [GVHD]. We previously reported that such angiogenic factors are indeed altered at the onset of acute graft-versus-host disease based upon samples from BMT CTN 0302 and 0802,” said Dr. Holtan of the University of Minnesota, Minneapolis. “Specifically, we found that repair factors of epidermal growth factor and VEGF-A are low at the onset of acute GVHD, and that damage-associated angiogenic factors are high at the onset of acute graft-versus-host disease.”
These damage-associated factors include follistatin, endoglin, placental growth factor, and angiopoietin-2, she added.
Based on the previous results, Dr. Holtan and her colleagues hypothesized that a pattern of tissue damage as illustrated by these markers at 28 days after treatment would be associated with 1-year nonrelapse mortality.
Of 221 patients from BMT CTN 0402 with pretreatment and day 28 plasma samples available for analysis, 25 had died at 1 year of causes unrelated to relapse. In a univariate analysis, nonrelapse mortality was associated with levels of follistatin, endoglin, and angiopoietin-2. When combined to assess for an overall pattern of damage, only follistatin and endoglin were significantly associated with nonrelapse mortality.
The relative risk of death unrelated to relapse was 4.5-fold higher in patients with the highest score (score of 3) on multivariate regression analysis of follistatin and endoglin levels. Grade II-IV acute GVHD was not significantly associated with 1-year nonrelapse mortality in multivariate analyses, but age over 50 years was.
“Notably, the composite score was a better predictor than any factor alone,” Dr. Holtan said.
The composite score was also predictive of the development of acute GVHD.
“We found that a moderate score of 2 was associated with a 2.3-fold increased risk of acute GVHD prior to day 100. Interestingly, the higher score [3] was not associated with acute GVHD. There was no association of the composite score with chronic GVHD,” she said.
The risk of nonrelapse mortality was less than 10% in patients with a composite score of 1.
Among patients in the study with a score of 3, more than half of the deaths were related to organ toxicity, including liver failure and respiratory failure, which were predominantly infection-related. Those with a low composite score had very few deaths associated with organ toxicity, she noted.
While there are many unanswered questions, these findings highlight possible opportunities to improve survival after allogeneic hematopoietic cell transplantation that warrant further study, she said.
“We need to learn how to constrain this angiogenic inflammatory response with the ultimate goal of hopefully identifying novel treatment strategies to mitigate nonrelapse mortality in our patients,” she concluded.
Dr. Holtan is an investigator for Alexion and is site principal investigator on the GI GVHD clinical trial.
ORLANDO – A composite score based on day 28 plasma levels of the angiogenic factors follistatin and endoglin predicts 1-year nonrelapse mortality in patients who have undergone myeloablative allogeneic hematopoietic cell transplantation, based on findings from the randomized Blood and Marrow Transplant Clinical Trials Network acute graft-versus-host prophylaxis study 0402 (BMT CTN 0402).
Elevations in these factors at day 28 may reflect susceptibility to regimen-related and other toxicities that adversely affect tissue repair and survival, Shernan Holtan, 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.
“Without important trophic angiogenic factors, the body may not be able to heal well after injury such as graft-versus-host disease [GVHD]. We previously reported that such angiogenic factors are indeed altered at the onset of acute graft-versus-host disease based upon samples from BMT CTN 0302 and 0802,” said Dr. Holtan of the University of Minnesota, Minneapolis. “Specifically, we found that repair factors of epidermal growth factor and VEGF-A are low at the onset of acute GVHD, and that damage-associated angiogenic factors are high at the onset of acute graft-versus-host disease.”
These damage-associated factors include follistatin, endoglin, placental growth factor, and angiopoietin-2, she added.
Based on the previous results, Dr. Holtan and her colleagues hypothesized that a pattern of tissue damage as illustrated by these markers at 28 days after treatment would be associated with 1-year nonrelapse mortality.
Of 221 patients from BMT CTN 0402 with pretreatment and day 28 plasma samples available for analysis, 25 had died at 1 year of causes unrelated to relapse. In a univariate analysis, nonrelapse mortality was associated with levels of follistatin, endoglin, and angiopoietin-2. When combined to assess for an overall pattern of damage, only follistatin and endoglin were significantly associated with nonrelapse mortality.
The relative risk of death unrelated to relapse was 4.5-fold higher in patients with the highest score (score of 3) on multivariate regression analysis of follistatin and endoglin levels. Grade II-IV acute GVHD was not significantly associated with 1-year nonrelapse mortality in multivariate analyses, but age over 50 years was.
“Notably, the composite score was a better predictor than any factor alone,” Dr. Holtan said.
The composite score was also predictive of the development of acute GVHD.
“We found that a moderate score of 2 was associated with a 2.3-fold increased risk of acute GVHD prior to day 100. Interestingly, the higher score [3] was not associated with acute GVHD. There was no association of the composite score with chronic GVHD,” she said.
The risk of nonrelapse mortality was less than 10% in patients with a composite score of 1.
Among patients in the study with a score of 3, more than half of the deaths were related to organ toxicity, including liver failure and respiratory failure, which were predominantly infection-related. Those with a low composite score had very few deaths associated with organ toxicity, she noted.
While there are many unanswered questions, these findings highlight possible opportunities to improve survival after allogeneic hematopoietic cell transplantation that warrant further study, she said.
“We need to learn how to constrain this angiogenic inflammatory response with the ultimate goal of hopefully identifying novel treatment strategies to mitigate nonrelapse mortality in our patients,” she concluded.
Dr. Holtan is an investigator for Alexion and is site principal investigator on the GI GVHD clinical trial.
AT THE 2017 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Patients with a composite score of 3 had a 4.5-fold higher relative risk of nonrelapse mortality.
Data source: The randomized BMT CTN 0402 study of 221 patients.
Disclosures: Dr. Holtan is an investigator for Alexion and is site principal investigator on the GI GVHD clinical trial.
MDS gene mutations predict response to HSCT
Genetic mutations in blood samples may predict outcomes and guide treatment for patients of all ages who have myelodysplastic syndrome and are undergoing hematopoietic stem-cell transplantation, according to a report published online Feb. 8 in the New England Journal of Medicine.
Allogeneic hematopoietic stem-cell transplantation is the only potentially curative therapy currently available for myelodysplastic syndrome (MDS), but mortality due to relapse and to transplant-related complications is high. “Predicting which patients are most likely to benefit from transplantation is thus a central challenge,” and identifying patients most likely to relapse could help clinicians refine conditioning regimens and relapse-prevention strategies, said R. Coleman Lindsley, MD, PhD, of the division of hematological malignancies, Dana-Farber Cancer Institute, Boston, and his associates.
The analyses included targeted sequencing of 129 genes known or suspected to be involved in the pathogenesis of myeloid cancers or syndromes related to bone marrow failure. Approximately 80% of the study participants were found to have at least one such driver mutation, with a median of two mutations per patient.
Mutations in the TP53 gene turned out to be the single most powerful predictor of survival after transplantation, independent of factors such as patient age, performance status, and hematologic variables. Moreover, intensive (myeloablative) conditioning regimens did not attenuate this effect, “a finding that is consistent with clinical and experimental evidence showing TP53 mutation-mediated chemoresistance,” Dr. Lindsley and his associates said.
“Our data suggest that escalating the intensity of the conditioning regimen in order to improve outcomes in patients with TP53-mutated MDS will not be successful. ... These patients, who have an exceptionally high risk of relapse-related death after transplantation, should be considered for investigative approaches to conditioning or new relapse-prevention strategies after transplantation,” they added.
Among patients over age 40, mutations in the RAS pathway were associated with a significantly elevated risk of early relapse – an outcome that might be ameliorated by more intensive conditioning. “RAS-pathway mutations may thus reflect the presence of low-volume but biologically transformed disease that, without adequate cytoreduction before transplantation, outpaces the development of effective graft-versus-leukemia activity,” the investigators said.
However, this association between RAS mutations and relapse was not seen in patients younger than age 40 years, they noted.
Conversely, JAK2 mutations were associated with a higher rate of death without relapse but not a higher rate of relapse. And this association was not affected by conditioning intensity. Although the mechanism of such an effect is not yet known, early death without relapse may be driven by factors that are susceptible to targeting by JAK2 inhibitors. In addition, minimizing treatment toxicity should be the focus of treatment in patients who carry JAK2 mutations, since their poor survival rate is driven by deaths unrelated to relapse, Dr. Lindsley and his associates said.
Mutations in the PPM1D gene, especially when accompanied by TP53 mutations, were strongly associated with previous exposure to leukemogenic therapies. “PPM1D encodes a serine-threonine protein phosphatase that regulates the cellular response to environmental stress, in part by means of inhibition of TP53 activity, which suggests that TP53 and PPM1D mutations represent convergent mechanisms of clonal survival in the context of leukemogenic exposures,” the investigators said.
“Our results... provide strong genetic evidence of the role of PPM1D mutations in the pathogenesis of therapy-related myelodysplastic syndromes.”
Mutations in the SBDS gene, which has been linked to Shwachman-Diamond syndrome, were “unexpectedly common” in young-adult patients and were associated with a poor prognosis. (Shwachman-Diamond syndrome is a rare congenital syndrome of bone-marrow failure.) This finding suggests that early stem-cell transplantation should be considered for patients who have this disorder, since transplantation after full-blown MDS develops “may not offer long-term benefit.”
Genetic mutations in blood samples may predict outcomes and guide treatment for patients of all ages who have myelodysplastic syndrome and are undergoing hematopoietic stem-cell transplantation, according to a report published online Feb. 8 in the New England Journal of Medicine.
Allogeneic hematopoietic stem-cell transplantation is the only potentially curative therapy currently available for myelodysplastic syndrome (MDS), but mortality due to relapse and to transplant-related complications is high. “Predicting which patients are most likely to benefit from transplantation is thus a central challenge,” and identifying patients most likely to relapse could help clinicians refine conditioning regimens and relapse-prevention strategies, said R. Coleman Lindsley, MD, PhD, of the division of hematological malignancies, Dana-Farber Cancer Institute, Boston, and his associates.
The analyses included targeted sequencing of 129 genes known or suspected to be involved in the pathogenesis of myeloid cancers or syndromes related to bone marrow failure. Approximately 80% of the study participants were found to have at least one such driver mutation, with a median of two mutations per patient.
Mutations in the TP53 gene turned out to be the single most powerful predictor of survival after transplantation, independent of factors such as patient age, performance status, and hematologic variables. Moreover, intensive (myeloablative) conditioning regimens did not attenuate this effect, “a finding that is consistent with clinical and experimental evidence showing TP53 mutation-mediated chemoresistance,” Dr. Lindsley and his associates said.
“Our data suggest that escalating the intensity of the conditioning regimen in order to improve outcomes in patients with TP53-mutated MDS will not be successful. ... These patients, who have an exceptionally high risk of relapse-related death after transplantation, should be considered for investigative approaches to conditioning or new relapse-prevention strategies after transplantation,” they added.
Among patients over age 40, mutations in the RAS pathway were associated with a significantly elevated risk of early relapse – an outcome that might be ameliorated by more intensive conditioning. “RAS-pathway mutations may thus reflect the presence of low-volume but biologically transformed disease that, without adequate cytoreduction before transplantation, outpaces the development of effective graft-versus-leukemia activity,” the investigators said.
However, this association between RAS mutations and relapse was not seen in patients younger than age 40 years, they noted.
Conversely, JAK2 mutations were associated with a higher rate of death without relapse but not a higher rate of relapse. And this association was not affected by conditioning intensity. Although the mechanism of such an effect is not yet known, early death without relapse may be driven by factors that are susceptible to targeting by JAK2 inhibitors. In addition, minimizing treatment toxicity should be the focus of treatment in patients who carry JAK2 mutations, since their poor survival rate is driven by deaths unrelated to relapse, Dr. Lindsley and his associates said.
Mutations in the PPM1D gene, especially when accompanied by TP53 mutations, were strongly associated with previous exposure to leukemogenic therapies. “PPM1D encodes a serine-threonine protein phosphatase that regulates the cellular response to environmental stress, in part by means of inhibition of TP53 activity, which suggests that TP53 and PPM1D mutations represent convergent mechanisms of clonal survival in the context of leukemogenic exposures,” the investigators said.
“Our results... provide strong genetic evidence of the role of PPM1D mutations in the pathogenesis of therapy-related myelodysplastic syndromes.”
Mutations in the SBDS gene, which has been linked to Shwachman-Diamond syndrome, were “unexpectedly common” in young-adult patients and were associated with a poor prognosis. (Shwachman-Diamond syndrome is a rare congenital syndrome of bone-marrow failure.) This finding suggests that early stem-cell transplantation should be considered for patients who have this disorder, since transplantation after full-blown MDS develops “may not offer long-term benefit.”
Genetic mutations in blood samples may predict outcomes and guide treatment for patients of all ages who have myelodysplastic syndrome and are undergoing hematopoietic stem-cell transplantation, according to a report published online Feb. 8 in the New England Journal of Medicine.
Allogeneic hematopoietic stem-cell transplantation is the only potentially curative therapy currently available for myelodysplastic syndrome (MDS), but mortality due to relapse and to transplant-related complications is high. “Predicting which patients are most likely to benefit from transplantation is thus a central challenge,” and identifying patients most likely to relapse could help clinicians refine conditioning regimens and relapse-prevention strategies, said R. Coleman Lindsley, MD, PhD, of the division of hematological malignancies, Dana-Farber Cancer Institute, Boston, and his associates.
The analyses included targeted sequencing of 129 genes known or suspected to be involved in the pathogenesis of myeloid cancers or syndromes related to bone marrow failure. Approximately 80% of the study participants were found to have at least one such driver mutation, with a median of two mutations per patient.
Mutations in the TP53 gene turned out to be the single most powerful predictor of survival after transplantation, independent of factors such as patient age, performance status, and hematologic variables. Moreover, intensive (myeloablative) conditioning regimens did not attenuate this effect, “a finding that is consistent with clinical and experimental evidence showing TP53 mutation-mediated chemoresistance,” Dr. Lindsley and his associates said.
“Our data suggest that escalating the intensity of the conditioning regimen in order to improve outcomes in patients with TP53-mutated MDS will not be successful. ... These patients, who have an exceptionally high risk of relapse-related death after transplantation, should be considered for investigative approaches to conditioning or new relapse-prevention strategies after transplantation,” they added.
Among patients over age 40, mutations in the RAS pathway were associated with a significantly elevated risk of early relapse – an outcome that might be ameliorated by more intensive conditioning. “RAS-pathway mutations may thus reflect the presence of low-volume but biologically transformed disease that, without adequate cytoreduction before transplantation, outpaces the development of effective graft-versus-leukemia activity,” the investigators said.
However, this association between RAS mutations and relapse was not seen in patients younger than age 40 years, they noted.
Conversely, JAK2 mutations were associated with a higher rate of death without relapse but not a higher rate of relapse. And this association was not affected by conditioning intensity. Although the mechanism of such an effect is not yet known, early death without relapse may be driven by factors that are susceptible to targeting by JAK2 inhibitors. In addition, minimizing treatment toxicity should be the focus of treatment in patients who carry JAK2 mutations, since their poor survival rate is driven by deaths unrelated to relapse, Dr. Lindsley and his associates said.
Mutations in the PPM1D gene, especially when accompanied by TP53 mutations, were strongly associated with previous exposure to leukemogenic therapies. “PPM1D encodes a serine-threonine protein phosphatase that regulates the cellular response to environmental stress, in part by means of inhibition of TP53 activity, which suggests that TP53 and PPM1D mutations represent convergent mechanisms of clonal survival in the context of leukemogenic exposures,” the investigators said.
“Our results... provide strong genetic evidence of the role of PPM1D mutations in the pathogenesis of therapy-related myelodysplastic syndromes.”
Mutations in the SBDS gene, which has been linked to Shwachman-Diamond syndrome, were “unexpectedly common” in young-adult patients and were associated with a poor prognosis. (Shwachman-Diamond syndrome is a rare congenital syndrome of bone-marrow failure.) This finding suggests that early stem-cell transplantation should be considered for patients who have this disorder, since transplantation after full-blown MDS develops “may not offer long-term benefit.”
Key clinical point: Genetic mutations in blood samples may predict outcomes and guide treatment for patients of all ages who have myelodysplastic syndrome and are undergoing hematopoietic stem-cell transplantation.
Key numerical finding: Approximately 80% of the study participants were found to have at least one driver mutation, with a median of two such mutations per patient.
Data source: Targeted mutational analyses of banked blood samples from 1,514 patients treated at 130 transplantation centers in the U.S. and Germany.
Disclosures: This study was supported by the Edward P. Evans Foundation, the Harvard Catalyst Program, the National Marrow Donor Program, the National Institutes of Health, and the Leukemia and Lymphoma Society. Dr. Lindsley reported ties to Takeda, and one of his associates reported ties to Celgene, Genoptix, and H3 Biomedicine.