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Coming soon: CAR T-cell approvals in multiple myeloma
, and will “completely transform oncology,” according to Carl June, MD.
That approval is anticipated sometime in 2019.
“Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells,” Dr. June, the Richard W. Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia, said in an interview.
The first treated patient in a trial of a novel anti-B-cell maturation antigen (BCMA)-specific CAR T-cell therapy (CART-BCMA) developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset.
Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas recently outed himself as that first patient, announcing in a Feb. 14, 2018, UT Southwestern press report that CART-BCMA saved his life.
Dr. Wright, who holds the Southland Financial Corporation Distinguished Chair in Geriatrics at UT Southwestern, was diagnosed with multiple myeloma about 12 years ago and failed 11 prior chemotherapies before he was enrolled in the CART-BCMA trial.
“Now he considers himself cured,” Dr. June said.
More than 2 years after receiving CART-BCMA he remains cancer free, and is now conducting CAR T-cell-related research in his lab at UT Southwestern in an effort to broaden the effectiveness of current CAR T-cell therapies. Specifically, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, as most patients who fail CAR T-cell therapy are elderly patients who might have terminally short telomeres, UT Southwestern reported.
The ongoing University of Pennsylvania trial led by Adam D. Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the American Society of Hematology (ASH) annual meeting in 2016, and multiple companies are currently pursuing registration trials for CAR T therapies in myeloma, Dr. June said.
Among them are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. That product was granted breakthrough therapy designation by the Food and Drug Administration in November 2017, and will thus receive expedited review. It has also been fast-tracked in Europe.
The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial. Updated findings from that trial were presented in December 2017 at ASH and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 106 CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.
Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells.
Janssen Biotech Inc. (a Johnson & Johnson company) and Legend Biotech USA Inc./Legend Biotech Ireland Limited (of Genscript Biotech Corporation) have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr. June said.
The companies announced in December that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate.
LCAR-B38M is currently accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
The “race between companies” for a CAR T myeloma approval will lead to a welcome addition to the treatment armamentarium, because while myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr. June said.
Since many patients live with their disease for a long time, that can mean huge “financial toxicity” associated with treatment and patients still usually have “an awful outcome involving a long death,” he said.
“So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added, explaining that the first CAR T-cell therapy approved (tisagenlecleucel, in August 2017) was for pediatric acute lymphoblastic leukemia that had relapsed at least twice. “That’s only about 600 kids a year in the U.S., so it’s an ultra-orphan market,” he said.
With the subsequent approval of axicabtagene ciloleucel (in October 2017) and the anticipated myeloma approval, CAR T-cell therapy will move away from orphan status.
“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s.
Early on, there were only two places in the country where a patient could get a bone marrow transplant – Fred Hutchinson Cancer Center in Seattle and Johns Hopkins University in Baltimore. “Everyone said ‘you’ll never be able to do it routinely, it’s only at these two referral centers,’ because of the skill needed and the intensity of it,” he said. “But over the years, millions of transplants have now been done; they’re done at many community centers. And it’s the same thing with CARs; Novartis now has 30 centers and people have to be trained. It’s a new skill set, and it will take time,” he said.
That can be particularly frustrating because there are many patients with diseases that “might benefit in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr. June noted.
“There’s more demand than availability, and it’s going to take awhile ... it’s like liver transplants – there aren’t enough donors to go around, so people die, they get on lists, and it’s really hard to see that, but eventually it will get solved,” he said, adding that the solution will most likely involve the complementary use of off-the-shelf CAR T cells in certain patients to induce remission and perhaps provide a bridge to some other definitive therapy, and ultra-personalized CAR T therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.
CRISPR-Cas9 gene editing is also being looked at as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute–funded NYCE study, Dr. June said.
“We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial,” he said. “We just opened and we’re screening patients now.”
Dr. June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.
, and will “completely transform oncology,” according to Carl June, MD.
That approval is anticipated sometime in 2019.
“Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells,” Dr. June, the Richard W. Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia, said in an interview.
The first treated patient in a trial of a novel anti-B-cell maturation antigen (BCMA)-specific CAR T-cell therapy (CART-BCMA) developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset.
Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas recently outed himself as that first patient, announcing in a Feb. 14, 2018, UT Southwestern press report that CART-BCMA saved his life.
Dr. Wright, who holds the Southland Financial Corporation Distinguished Chair in Geriatrics at UT Southwestern, was diagnosed with multiple myeloma about 12 years ago and failed 11 prior chemotherapies before he was enrolled in the CART-BCMA trial.
“Now he considers himself cured,” Dr. June said.
More than 2 years after receiving CART-BCMA he remains cancer free, and is now conducting CAR T-cell-related research in his lab at UT Southwestern in an effort to broaden the effectiveness of current CAR T-cell therapies. Specifically, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, as most patients who fail CAR T-cell therapy are elderly patients who might have terminally short telomeres, UT Southwestern reported.
The ongoing University of Pennsylvania trial led by Adam D. Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the American Society of Hematology (ASH) annual meeting in 2016, and multiple companies are currently pursuing registration trials for CAR T therapies in myeloma, Dr. June said.
Among them are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. That product was granted breakthrough therapy designation by the Food and Drug Administration in November 2017, and will thus receive expedited review. It has also been fast-tracked in Europe.
The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial. Updated findings from that trial were presented in December 2017 at ASH and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 106 CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.
Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells.
Janssen Biotech Inc. (a Johnson & Johnson company) and Legend Biotech USA Inc./Legend Biotech Ireland Limited (of Genscript Biotech Corporation) have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr. June said.
The companies announced in December that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate.
LCAR-B38M is currently accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
The “race between companies” for a CAR T myeloma approval will lead to a welcome addition to the treatment armamentarium, because while myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr. June said.
Since many patients live with their disease for a long time, that can mean huge “financial toxicity” associated with treatment and patients still usually have “an awful outcome involving a long death,” he said.
“So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added, explaining that the first CAR T-cell therapy approved (tisagenlecleucel, in August 2017) was for pediatric acute lymphoblastic leukemia that had relapsed at least twice. “That’s only about 600 kids a year in the U.S., so it’s an ultra-orphan market,” he said.
With the subsequent approval of axicabtagene ciloleucel (in October 2017) and the anticipated myeloma approval, CAR T-cell therapy will move away from orphan status.
“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s.
Early on, there were only two places in the country where a patient could get a bone marrow transplant – Fred Hutchinson Cancer Center in Seattle and Johns Hopkins University in Baltimore. “Everyone said ‘you’ll never be able to do it routinely, it’s only at these two referral centers,’ because of the skill needed and the intensity of it,” he said. “But over the years, millions of transplants have now been done; they’re done at many community centers. And it’s the same thing with CARs; Novartis now has 30 centers and people have to be trained. It’s a new skill set, and it will take time,” he said.
That can be particularly frustrating because there are many patients with diseases that “might benefit in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr. June noted.
“There’s more demand than availability, and it’s going to take awhile ... it’s like liver transplants – there aren’t enough donors to go around, so people die, they get on lists, and it’s really hard to see that, but eventually it will get solved,” he said, adding that the solution will most likely involve the complementary use of off-the-shelf CAR T cells in certain patients to induce remission and perhaps provide a bridge to some other definitive therapy, and ultra-personalized CAR T therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.
CRISPR-Cas9 gene editing is also being looked at as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute–funded NYCE study, Dr. June said.
“We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial,” he said. “We just opened and we’re screening patients now.”
Dr. June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.
, and will “completely transform oncology,” according to Carl June, MD.
That approval is anticipated sometime in 2019.
“Myeloma is the most common blood cancer in adults, and there’s never been a curative therapy, but now there is a subset of patients who look like they’re cured with CAR T cells,” Dr. June, the Richard W. Vague Professor in Immunotherapy and a pioneer in CAR T-cell research at the University of Pennsylvania, Philadelphia, said in an interview.
The first treated patient in a trial of a novel anti-B-cell maturation antigen (BCMA)-specific CAR T-cell therapy (CART-BCMA) developed by University of Pennsylvania researchers in collaboration with Novartis is part of that subset.
Woodring Wright, MD, a professor of cell biology and medicine at the University of Texas Southwestern Medical Center (UT Southwestern) in Dallas recently outed himself as that first patient, announcing in a Feb. 14, 2018, UT Southwestern press report that CART-BCMA saved his life.
Dr. Wright, who holds the Southland Financial Corporation Distinguished Chair in Geriatrics at UT Southwestern, was diagnosed with multiple myeloma about 12 years ago and failed 11 prior chemotherapies before he was enrolled in the CART-BCMA trial.
“Now he considers himself cured,” Dr. June said.
More than 2 years after receiving CART-BCMA he remains cancer free, and is now conducting CAR T-cell-related research in his lab at UT Southwestern in an effort to broaden the effectiveness of current CAR T-cell therapies. Specifically, he is looking at whether the small percentage of patients in whom CAR T-cell therapy does not work might benefit from telomerase to lengthen telomeres, as most patients who fail CAR T-cell therapy are elderly patients who might have terminally short telomeres, UT Southwestern reported.
The ongoing University of Pennsylvania trial led by Adam D. Cohen, MD, director of myeloma immunotherapy at the Abramson Cancer Center, has an overall response rate of 64%; initial phase 1 efficacy and safety results were reported at the American Society of Hematology (ASH) annual meeting in 2016, and multiple companies are currently pursuing registration trials for CAR T therapies in myeloma, Dr. June said.
Among them are bluebird bio and Celgene, which together are developing an anti-BCMA CAR T-cell therapy known as bb2121. That product was granted breakthrough therapy designation by the Food and Drug Administration in November 2017, and will thus receive expedited review. It has also been fast-tracked in Europe.
The decision to fast-track bb2121 in the United States was based on preliminary results from the CRB-410 trial. Updated findings from that trial were presented in December 2017 at ASH and showed an overall response rate of 94% in 21 patients, with 17 of 18 patients who received doses above 50 x 106 CAR+ T cells having an overall response, and 10 of the 18 achieving complete remission. The progression-free survival rates were 81% at 6 months, and 71% at 9 months, with responses deepening over time. The complete response rates were 27% and 56% in May and October of 2017, respectively.
Responses were durable, lasting more than 1 year in several patients, the investigators reported. Phase 2 of the trial – the global pivotal KarMMA trial – is currently enrolling and will dose patients at between 150 and 350 x 106 CAR+ T cells.
Janssen Biotech Inc. (a Johnson & Johnson company) and Legend Biotech USA Inc./Legend Biotech Ireland Limited (of Genscript Biotech Corporation) have also joined forces to develop an anti-BCMA CAR T-cell product for multiple myeloma, Dr. June said.
The companies announced in December that they had entered into “a worldwide collaboration and license agreement” to develop the CAR T-cell drug candidate.
LCAR-B38M is currently accepted for review by the China Food and Drug Administration and is in the planning phase of clinical studies in the United States for multiple myeloma, according to that announcement.
The “race between companies” for a CAR T myeloma approval will lead to a welcome addition to the treatment armamentarium, because while myeloma represents only about 2% of all cancers, it is responsible for 7% of cancer costs, Dr. June said.
Since many patients live with their disease for a long time, that can mean huge “financial toxicity” associated with treatment and patients still usually have “an awful outcome involving a long death,” he said.
“So CAR T-cell therapy for myeloma will bring a huge change to the practice of oncology,” he added, explaining that the first CAR T-cell therapy approved (tisagenlecleucel, in August 2017) was for pediatric acute lymphoblastic leukemia that had relapsed at least twice. “That’s only about 600 kids a year in the U.S., so it’s an ultra-orphan market,” he said.
With the subsequent approval of axicabtagene ciloleucel (in October 2017) and the anticipated myeloma approval, CAR T-cell therapy will move away from orphan status.
“There are a lot of difficulties whenever you change to something new,” he said, comparing the CAR T-cell therapy evolution to that of bone marrow transplantation in the 1980s.
Early on, there were only two places in the country where a patient could get a bone marrow transplant – Fred Hutchinson Cancer Center in Seattle and Johns Hopkins University in Baltimore. “Everyone said ‘you’ll never be able to do it routinely, it’s only at these two referral centers,’ because of the skill needed and the intensity of it,” he said. “But over the years, millions of transplants have now been done; they’re done at many community centers. And it’s the same thing with CARs; Novartis now has 30 centers and people have to be trained. It’s a new skill set, and it will take time,” he said.
That can be particularly frustrating because there are many patients with diseases that “might benefit in a major way” from CAR T-cell therapy, but who can’t get on a clinical trial, Dr. June noted.
“There’s more demand than availability, and it’s going to take awhile ... it’s like liver transplants – there aren’t enough donors to go around, so people die, they get on lists, and it’s really hard to see that, but eventually it will get solved,” he said, adding that the solution will most likely involve the complementary use of off-the-shelf CAR T cells in certain patients to induce remission and perhaps provide a bridge to some other definitive therapy, and ultra-personalized CAR T therapy in others, as well as combinations that include CAR T cells and targeted agents or checkpoint inhibitors.
CRISPR-Cas9 gene editing is also being looked at as a tool for engineering multiple myeloma cellular immunotherapy (and other cancer treatments), as in the Parker Institute–funded NYCE study, Dr. June said.
“We’re actually removing the [programmed death-1] gene and the T-cell receptors ... it shows enormous potential for gene editing. CRISPR is going to be used for a lot of things, but the first use is with T-cell therapies, so we’re really excited about that trial,” he said. “We just opened and we’re screening patients now.”
Dr. June reported royalties and research funding from Novartis and an ownership interest in Tmunity Therapeutics.
Study: Stick with TMP-SMX for posttransplant PJP prophylaxis
NEWPORT BEACH, CALIF. – Use of atovaquone or pentamidine for Pneumocystis jiroveci pneumonia (PJP) prophylaxis was associated with an increased incidence of nocardiosis in allogeneic hematopoietic stem call transplant (HSCT) recipients at the University of California, Los Angeles, according to a review of patient records.
Of 10 cases of late-onset nocardiosis identified among patients who received HSCT between Jan. 1, 2000, and Aug. 30, 2017, 9 cases occurred in 411 patients (2.2%) treated between 2012 and 2017 – a period of increased use of atovaquone prophylaxis, compared with only 1 in 575 patients (0.17%) treated in the prior 12 years when trimethoprim-sulfamethoxazole (TMP-SMX) was used for prophylaxis, Alfonso Molina reported in a poster at the Acute Leukemia Forum of Hemedicus.
None of the 575 patients treated between 2000 and 2012, versus 119 of the 411 treated after 2012, received atovaquone, he reported.
To assess the potential relationship between the use of atovaquone and the increased incidence of nocardiosis, he and his colleagues reviewed patient medical records and UCLA Clinical Microbiology Laboratory culture results.
Nocardiosis occurred mainly in patients on high doses of corticosteroids for graft-versus-host disease, and 8 of the 10 affected patients were not receiving TMP-SMX for PJP prophylaxis; 7 were on atovaquone, and 1 was on intravenous pentamidine, Mr. Molina said.
The findings suggest that TMP-SMX should remain the agent of choice for PJP prophylaxis in HSCT recipients and have prompted a return to the older protocol of high-dose TMP-SMX for this purpose at UCLA, he said.
“Unless a patient is totally intolerant of TMP-SMX, prophylaxis with atovaquone or pentamidine should be avoided,” he concluded.
Mr. Molina reported having no financial disclosures. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
SOURCE: Molina A et al., ALF 2018, Poster Session.
NEWPORT BEACH, CALIF. – Use of atovaquone or pentamidine for Pneumocystis jiroveci pneumonia (PJP) prophylaxis was associated with an increased incidence of nocardiosis in allogeneic hematopoietic stem call transplant (HSCT) recipients at the University of California, Los Angeles, according to a review of patient records.
Of 10 cases of late-onset nocardiosis identified among patients who received HSCT between Jan. 1, 2000, and Aug. 30, 2017, 9 cases occurred in 411 patients (2.2%) treated between 2012 and 2017 – a period of increased use of atovaquone prophylaxis, compared with only 1 in 575 patients (0.17%) treated in the prior 12 years when trimethoprim-sulfamethoxazole (TMP-SMX) was used for prophylaxis, Alfonso Molina reported in a poster at the Acute Leukemia Forum of Hemedicus.
None of the 575 patients treated between 2000 and 2012, versus 119 of the 411 treated after 2012, received atovaquone, he reported.
To assess the potential relationship between the use of atovaquone and the increased incidence of nocardiosis, he and his colleagues reviewed patient medical records and UCLA Clinical Microbiology Laboratory culture results.
Nocardiosis occurred mainly in patients on high doses of corticosteroids for graft-versus-host disease, and 8 of the 10 affected patients were not receiving TMP-SMX for PJP prophylaxis; 7 were on atovaquone, and 1 was on intravenous pentamidine, Mr. Molina said.
The findings suggest that TMP-SMX should remain the agent of choice for PJP prophylaxis in HSCT recipients and have prompted a return to the older protocol of high-dose TMP-SMX for this purpose at UCLA, he said.
“Unless a patient is totally intolerant of TMP-SMX, prophylaxis with atovaquone or pentamidine should be avoided,” he concluded.
Mr. Molina reported having no financial disclosures. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
SOURCE: Molina A et al., ALF 2018, Poster Session.
NEWPORT BEACH, CALIF. – Use of atovaquone or pentamidine for Pneumocystis jiroveci pneumonia (PJP) prophylaxis was associated with an increased incidence of nocardiosis in allogeneic hematopoietic stem call transplant (HSCT) recipients at the University of California, Los Angeles, according to a review of patient records.
Of 10 cases of late-onset nocardiosis identified among patients who received HSCT between Jan. 1, 2000, and Aug. 30, 2017, 9 cases occurred in 411 patients (2.2%) treated between 2012 and 2017 – a period of increased use of atovaquone prophylaxis, compared with only 1 in 575 patients (0.17%) treated in the prior 12 years when trimethoprim-sulfamethoxazole (TMP-SMX) was used for prophylaxis, Alfonso Molina reported in a poster at the Acute Leukemia Forum of Hemedicus.
None of the 575 patients treated between 2000 and 2012, versus 119 of the 411 treated after 2012, received atovaquone, he reported.
To assess the potential relationship between the use of atovaquone and the increased incidence of nocardiosis, he and his colleagues reviewed patient medical records and UCLA Clinical Microbiology Laboratory culture results.
Nocardiosis occurred mainly in patients on high doses of corticosteroids for graft-versus-host disease, and 8 of the 10 affected patients were not receiving TMP-SMX for PJP prophylaxis; 7 were on atovaquone, and 1 was on intravenous pentamidine, Mr. Molina said.
The findings suggest that TMP-SMX should remain the agent of choice for PJP prophylaxis in HSCT recipients and have prompted a return to the older protocol of high-dose TMP-SMX for this purpose at UCLA, he said.
“Unless a patient is totally intolerant of TMP-SMX, prophylaxis with atovaquone or pentamidine should be avoided,” he concluded.
Mr. Molina reported having no financial disclosures. The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
SOURCE: Molina A et al., ALF 2018, Poster Session.
REPORTING FROM ALF 2018
Key clinical point:
Major finding: The incidence of nocardiosis was 2.2% during atovaquone use versus 0.17% prior to its use.
Study details: A retrospective review of records for 986 patients.
Disclosures: Mr. Molina reported having no financial disclosures.
Source: Molina A et al. ALF 2018, Poster Session.
High engraftment with new umbilical transplant technique
SALT LAKE CITY – Recipients of hematopoietic cell transplant with umbilical cord blood CD34+ cells expanded with an aryl hydrocarbon receptor (AHR) antagonist had a significantly higher rate of engraftment and comparable survival to a historical cohort of umbilical cord blood recipients.
The robust expansion of donor umbilical cord blood seen with the new technique opens the door for better use of umbilical cord blood inventory with superior human leukocyte antigen (HLA) matching, John Wagner, MD, said at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The new technique still shared the benefits of low rates of graft-versus-host disease (GVHD) and high survival that have been seen in previous umbilical cord blood transplants, with no significant difference in overall survival, relapse, or acute or chronic GVHD.
Compared to historical controls (n = 151), patients receiving the AHR antagonist–expanded umbilical cord blood (UCB) cells with myeloablative conditioning (n = 9) saw complete and more rapid engraftment (100% vs. 89% engraftment at a median 14 days vs. 23 days; P less than .01), reported Dr. Wagner of the University of Minnesota, Minneapolis.
These and other results came from two arms of a phase 2 trial of MGTA-456 (the working name of the AHR-expanded UCB cells). Twenty patients were to receive MGTA-456 derived from partially matched umbilical cord blood units after either myeloablative or nonmyeloablative conditioning; one patient in each arm had low expansion of UCB, so a total of 18 patients received MGTA-456. Each intervention arm was compared with a historical control arm that had received conventional UCB units.
In the myeloablative arm, patient demographics and disease characteristics were similar to the control cohort except that the MGTA-456 patients were significantly heavier (93.8 kg vs. 66.7 kg; P less than .04).
Platelet recovery also rebounded faster with MGTA-456 plus myeloablative conditioning than it did with historical controls: 89% of patients had platelet recovery by a median 46 days, compared with 71% with platelet recovery by a median 64 days in the historical cohort (P less than .01).
Patients achieved rapid complete chimerism if they received myeloablative conditioning, and they had rapid rebound of CD4 counts to at least 200 by 2-3 months posttransplant, Dr. Wagner reported.
The nonmyeloablative arm had a historical control cohort of 132 patients. Characteristics were similar between the two groups except that the MGTA-456 patients were older and more likely to have high-risk disease.
Again, all patients had rapid neutrophil recovery and saw 100% engraftment with MGTA-456. Median time to engraftment was 7 days with MGTA-456 and 15 days for the historical controls (P less than .01). Platelet recovery took longer for the MGTA-456 (median of 47 vs. 107 days), but the difference was not statistically significant.
Complete chimerism was achieved rapidly with the nonmyeloablative regimen as well, and CD4 recovery was brisk, as had been seen with myeloablative conditioning before MGTA-456 transplantation.
Compared with historical controls, “MGTA-456 retains the benefits of low chronic-graft-versus host disease and high survival despite higher disease risk and age” in the study group, Dr. Wagner said. There were no significant differences between the intervention and historical control arms of the nonmyeloablative study in acute or chronic GVHD, relapse, or overall survival.
The use of MGTA-456 occurs against the backdrop of a history of high survival rates with UCB transplantation – about 70% at 5 years, Dr. Wagner said. However, when conventional culture and expansion methods for UCB were used, the median time to engraftment had been reported to be 25 days with a 79% engraftment rate. This contrasts with the mean 13 days to engraftment for peripheral blood transplants and 18 days for bone marrow transplants. All of these transplant sources, regardless of whether the transplant was matched or mismatched, have engraftment rates of 92%-96%, said Dr. Wagner (Lancet Oncol. 2010; 11[7]:653-60).
When an AHR antagonist is used for UCB expansion, hematopoietic stem cell renewal is upped because cell differentiation is blocked, which means expansion is all driven toward hematopoietic stem cell self-renewal, Dr. Wagner said. Of the 36 available samples, MGTA-456 achieved a median 327-fold expansion of CD34+ cells, which enabled investigators to deliver a median CD34+ dose of 17.5 X 106 cells/kg.
The downstream effect of the robust expansion rates is that more cord blood will be available for transplantation, and HLA matches will improve, Dr. Wagner said. Using current expansion techniques, fewer than 5% of cord blood units have a total nucleated cell count sufficient for an adult 80 kg recipient, he said, adding that use of MGTA-456 could make more than 80% of cord blood units available for adults.
According to the UCB transplant history at the University of Minnesota – where Dr. Wagner directs the pediatric blood and marrow transplantation program – of the patients who received 4/6 HLA-matched cord blood, 63% would move to a 5/6 match, and 8% would move to a full HLA match with the MGTA-456 technique. Of patients who received 5/6-matched transplants, almost one in four (23%) would move to a full 6/6 match.
Dr. Wagner and his colleagues had previously shown that adding an AHR antagonist resulted in enhanced T-cell recovery and rapid and sustained engraftment (Science. 2010;329:1345-8).
The researchers then proceeded to a phase 1-2, first-in-human trial of MGTA-456 that used a myeloablative conditioning regimen that met its primary safety endpoint of a lack of infusional toxicity or primary/secondary graft failure (Cell Stem Cell. 2016;18:144-55).
For reasons of safety, this earlier study used a double-transplant platform in which one infusion was uncultured umbilical cord blood and the other was MGTA-456. This study showed rapid neutrophil recovery when MGTA-456 was infused, with median 10.5 days to recovery, compared with a median 26.5 days for historical controls (P less than .001).
Additionally, the study showed a 19-day decrease in duration of the initial hospitalization, and all patients who received MGTA-456 had successful engraftment, Dr. Wagner said. On the strength of these results, the current trials of MGTA-456 alone – with both nonmyeloablative and myeloablative conditioning – were approved.
Multicenter clinical trials of MGTA-456 transplantation are now planned for both malignant and nonmalignant diseases. Enrollment is currently open for a phase 2 clinical trial of MGTA for inherited metabolic disorders (NCT03406962).
The study was funded by Novartis and Magenta Therapeutics. Dr. Wagner reported no other relevant disclosures.
SOURCE: Wagner J et al. 2018 BMT Tandem Meetings, Abstract 4.
SALT LAKE CITY – Recipients of hematopoietic cell transplant with umbilical cord blood CD34+ cells expanded with an aryl hydrocarbon receptor (AHR) antagonist had a significantly higher rate of engraftment and comparable survival to a historical cohort of umbilical cord blood recipients.
The robust expansion of donor umbilical cord blood seen with the new technique opens the door for better use of umbilical cord blood inventory with superior human leukocyte antigen (HLA) matching, John Wagner, MD, said at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The new technique still shared the benefits of low rates of graft-versus-host disease (GVHD) and high survival that have been seen in previous umbilical cord blood transplants, with no significant difference in overall survival, relapse, or acute or chronic GVHD.
Compared to historical controls (n = 151), patients receiving the AHR antagonist–expanded umbilical cord blood (UCB) cells with myeloablative conditioning (n = 9) saw complete and more rapid engraftment (100% vs. 89% engraftment at a median 14 days vs. 23 days; P less than .01), reported Dr. Wagner of the University of Minnesota, Minneapolis.
These and other results came from two arms of a phase 2 trial of MGTA-456 (the working name of the AHR-expanded UCB cells). Twenty patients were to receive MGTA-456 derived from partially matched umbilical cord blood units after either myeloablative or nonmyeloablative conditioning; one patient in each arm had low expansion of UCB, so a total of 18 patients received MGTA-456. Each intervention arm was compared with a historical control arm that had received conventional UCB units.
In the myeloablative arm, patient demographics and disease characteristics were similar to the control cohort except that the MGTA-456 patients were significantly heavier (93.8 kg vs. 66.7 kg; P less than .04).
Platelet recovery also rebounded faster with MGTA-456 plus myeloablative conditioning than it did with historical controls: 89% of patients had platelet recovery by a median 46 days, compared with 71% with platelet recovery by a median 64 days in the historical cohort (P less than .01).
Patients achieved rapid complete chimerism if they received myeloablative conditioning, and they had rapid rebound of CD4 counts to at least 200 by 2-3 months posttransplant, Dr. Wagner reported.
The nonmyeloablative arm had a historical control cohort of 132 patients. Characteristics were similar between the two groups except that the MGTA-456 patients were older and more likely to have high-risk disease.
Again, all patients had rapid neutrophil recovery and saw 100% engraftment with MGTA-456. Median time to engraftment was 7 days with MGTA-456 and 15 days for the historical controls (P less than .01). Platelet recovery took longer for the MGTA-456 (median of 47 vs. 107 days), but the difference was not statistically significant.
Complete chimerism was achieved rapidly with the nonmyeloablative regimen as well, and CD4 recovery was brisk, as had been seen with myeloablative conditioning before MGTA-456 transplantation.
Compared with historical controls, “MGTA-456 retains the benefits of low chronic-graft-versus host disease and high survival despite higher disease risk and age” in the study group, Dr. Wagner said. There were no significant differences between the intervention and historical control arms of the nonmyeloablative study in acute or chronic GVHD, relapse, or overall survival.
The use of MGTA-456 occurs against the backdrop of a history of high survival rates with UCB transplantation – about 70% at 5 years, Dr. Wagner said. However, when conventional culture and expansion methods for UCB were used, the median time to engraftment had been reported to be 25 days with a 79% engraftment rate. This contrasts with the mean 13 days to engraftment for peripheral blood transplants and 18 days for bone marrow transplants. All of these transplant sources, regardless of whether the transplant was matched or mismatched, have engraftment rates of 92%-96%, said Dr. Wagner (Lancet Oncol. 2010; 11[7]:653-60).
When an AHR antagonist is used for UCB expansion, hematopoietic stem cell renewal is upped because cell differentiation is blocked, which means expansion is all driven toward hematopoietic stem cell self-renewal, Dr. Wagner said. Of the 36 available samples, MGTA-456 achieved a median 327-fold expansion of CD34+ cells, which enabled investigators to deliver a median CD34+ dose of 17.5 X 106 cells/kg.
The downstream effect of the robust expansion rates is that more cord blood will be available for transplantation, and HLA matches will improve, Dr. Wagner said. Using current expansion techniques, fewer than 5% of cord blood units have a total nucleated cell count sufficient for an adult 80 kg recipient, he said, adding that use of MGTA-456 could make more than 80% of cord blood units available for adults.
According to the UCB transplant history at the University of Minnesota – where Dr. Wagner directs the pediatric blood and marrow transplantation program – of the patients who received 4/6 HLA-matched cord blood, 63% would move to a 5/6 match, and 8% would move to a full HLA match with the MGTA-456 technique. Of patients who received 5/6-matched transplants, almost one in four (23%) would move to a full 6/6 match.
Dr. Wagner and his colleagues had previously shown that adding an AHR antagonist resulted in enhanced T-cell recovery and rapid and sustained engraftment (Science. 2010;329:1345-8).
The researchers then proceeded to a phase 1-2, first-in-human trial of MGTA-456 that used a myeloablative conditioning regimen that met its primary safety endpoint of a lack of infusional toxicity or primary/secondary graft failure (Cell Stem Cell. 2016;18:144-55).
For reasons of safety, this earlier study used a double-transplant platform in which one infusion was uncultured umbilical cord blood and the other was MGTA-456. This study showed rapid neutrophil recovery when MGTA-456 was infused, with median 10.5 days to recovery, compared with a median 26.5 days for historical controls (P less than .001).
Additionally, the study showed a 19-day decrease in duration of the initial hospitalization, and all patients who received MGTA-456 had successful engraftment, Dr. Wagner said. On the strength of these results, the current trials of MGTA-456 alone – with both nonmyeloablative and myeloablative conditioning – were approved.
Multicenter clinical trials of MGTA-456 transplantation are now planned for both malignant and nonmalignant diseases. Enrollment is currently open for a phase 2 clinical trial of MGTA for inherited metabolic disorders (NCT03406962).
The study was funded by Novartis and Magenta Therapeutics. Dr. Wagner reported no other relevant disclosures.
SOURCE: Wagner J et al. 2018 BMT Tandem Meetings, Abstract 4.
SALT LAKE CITY – Recipients of hematopoietic cell transplant with umbilical cord blood CD34+ cells expanded with an aryl hydrocarbon receptor (AHR) antagonist had a significantly higher rate of engraftment and comparable survival to a historical cohort of umbilical cord blood recipients.
The robust expansion of donor umbilical cord blood seen with the new technique opens the door for better use of umbilical cord blood inventory with superior human leukocyte antigen (HLA) matching, John Wagner, MD, said at a top abstracts session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The new technique still shared the benefits of low rates of graft-versus-host disease (GVHD) and high survival that have been seen in previous umbilical cord blood transplants, with no significant difference in overall survival, relapse, or acute or chronic GVHD.
Compared to historical controls (n = 151), patients receiving the AHR antagonist–expanded umbilical cord blood (UCB) cells with myeloablative conditioning (n = 9) saw complete and more rapid engraftment (100% vs. 89% engraftment at a median 14 days vs. 23 days; P less than .01), reported Dr. Wagner of the University of Minnesota, Minneapolis.
These and other results came from two arms of a phase 2 trial of MGTA-456 (the working name of the AHR-expanded UCB cells). Twenty patients were to receive MGTA-456 derived from partially matched umbilical cord blood units after either myeloablative or nonmyeloablative conditioning; one patient in each arm had low expansion of UCB, so a total of 18 patients received MGTA-456. Each intervention arm was compared with a historical control arm that had received conventional UCB units.
In the myeloablative arm, patient demographics and disease characteristics were similar to the control cohort except that the MGTA-456 patients were significantly heavier (93.8 kg vs. 66.7 kg; P less than .04).
Platelet recovery also rebounded faster with MGTA-456 plus myeloablative conditioning than it did with historical controls: 89% of patients had platelet recovery by a median 46 days, compared with 71% with platelet recovery by a median 64 days in the historical cohort (P less than .01).
Patients achieved rapid complete chimerism if they received myeloablative conditioning, and they had rapid rebound of CD4 counts to at least 200 by 2-3 months posttransplant, Dr. Wagner reported.
The nonmyeloablative arm had a historical control cohort of 132 patients. Characteristics were similar between the two groups except that the MGTA-456 patients were older and more likely to have high-risk disease.
Again, all patients had rapid neutrophil recovery and saw 100% engraftment with MGTA-456. Median time to engraftment was 7 days with MGTA-456 and 15 days for the historical controls (P less than .01). Platelet recovery took longer for the MGTA-456 (median of 47 vs. 107 days), but the difference was not statistically significant.
Complete chimerism was achieved rapidly with the nonmyeloablative regimen as well, and CD4 recovery was brisk, as had been seen with myeloablative conditioning before MGTA-456 transplantation.
Compared with historical controls, “MGTA-456 retains the benefits of low chronic-graft-versus host disease and high survival despite higher disease risk and age” in the study group, Dr. Wagner said. There were no significant differences between the intervention and historical control arms of the nonmyeloablative study in acute or chronic GVHD, relapse, or overall survival.
The use of MGTA-456 occurs against the backdrop of a history of high survival rates with UCB transplantation – about 70% at 5 years, Dr. Wagner said. However, when conventional culture and expansion methods for UCB were used, the median time to engraftment had been reported to be 25 days with a 79% engraftment rate. This contrasts with the mean 13 days to engraftment for peripheral blood transplants and 18 days for bone marrow transplants. All of these transplant sources, regardless of whether the transplant was matched or mismatched, have engraftment rates of 92%-96%, said Dr. Wagner (Lancet Oncol. 2010; 11[7]:653-60).
When an AHR antagonist is used for UCB expansion, hematopoietic stem cell renewal is upped because cell differentiation is blocked, which means expansion is all driven toward hematopoietic stem cell self-renewal, Dr. Wagner said. Of the 36 available samples, MGTA-456 achieved a median 327-fold expansion of CD34+ cells, which enabled investigators to deliver a median CD34+ dose of 17.5 X 106 cells/kg.
The downstream effect of the robust expansion rates is that more cord blood will be available for transplantation, and HLA matches will improve, Dr. Wagner said. Using current expansion techniques, fewer than 5% of cord blood units have a total nucleated cell count sufficient for an adult 80 kg recipient, he said, adding that use of MGTA-456 could make more than 80% of cord blood units available for adults.
According to the UCB transplant history at the University of Minnesota – where Dr. Wagner directs the pediatric blood and marrow transplantation program – of the patients who received 4/6 HLA-matched cord blood, 63% would move to a 5/6 match, and 8% would move to a full HLA match with the MGTA-456 technique. Of patients who received 5/6-matched transplants, almost one in four (23%) would move to a full 6/6 match.
Dr. Wagner and his colleagues had previously shown that adding an AHR antagonist resulted in enhanced T-cell recovery and rapid and sustained engraftment (Science. 2010;329:1345-8).
The researchers then proceeded to a phase 1-2, first-in-human trial of MGTA-456 that used a myeloablative conditioning regimen that met its primary safety endpoint of a lack of infusional toxicity or primary/secondary graft failure (Cell Stem Cell. 2016;18:144-55).
For reasons of safety, this earlier study used a double-transplant platform in which one infusion was uncultured umbilical cord blood and the other was MGTA-456. This study showed rapid neutrophil recovery when MGTA-456 was infused, with median 10.5 days to recovery, compared with a median 26.5 days for historical controls (P less than .001).
Additionally, the study showed a 19-day decrease in duration of the initial hospitalization, and all patients who received MGTA-456 had successful engraftment, Dr. Wagner said. On the strength of these results, the current trials of MGTA-456 alone – with both nonmyeloablative and myeloablative conditioning – were approved.
Multicenter clinical trials of MGTA-456 transplantation are now planned for both malignant and nonmalignant diseases. Enrollment is currently open for a phase 2 clinical trial of MGTA for inherited metabolic disorders (NCT03406962).
The study was funded by Novartis and Magenta Therapeutics. Dr. Wagner reported no other relevant disclosures.
SOURCE: Wagner J et al. 2018 BMT Tandem Meetings, Abstract 4.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: The engraftment rate was 100% with both myeloablative and nonmyeloablative conditioning.
Study details: A phase 2 trial of 20 patients receiving MGTA-456, compared with a historical cohort of umbilical cord blood hematopoietic cell transplant recipients.
Disclosures: The study was sponsored by Novartis and Magenta Therapeutics. Dr. Wagner reported no other conflicts of interest.
Source: Wagner J et al. 2018 BMT Tandem Meetings, Abstract 4.
Posttransplant cyclophosphamide helped reduce GVHD rates
SALT LAKE CITY – The combination of mycophenolate mofetil, tacrolimus, and posttransplant cyclophosphamide outperformed other prophylaxis regimens at reducing graft versus host disease with relapse-free survival in a multicenter trial.
The trial’s primary aim was to compare rates of post–hematopoietic stem cell transplant GVHD-free and relapse-free survival (GRFS) in the three study arms, compared with the tacrolimus/methotrexate group, who were receiving a “contemporary control,” Javier Bolaños-Meade, MD, said during a late-breaking abstract session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide group had a hazard ratio of 0.72 for reaching the primary endpoint – GRFS (95% confidence interval, 0.55-0.94; P = .04), compared with patients receiving the control regimen. In the study, GRFS was defined as the amount of time elapsed between transplant and any of: grade III-IV acute GVHD, chronic GVHD severe enough to require systemic therapy, disease relapse or progression, or death. Grade III-IV acute GVHD and GVHD survival were superior with mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide, compared with the control (P = .006 and .01, respectively).
The phase 2 trial enrolled adults aged 18-75 years who had a malignant disease and a matched donor, and were slated to receive reduced intensity conditioning. The study randomized patients 1:1:1 to one of three experimental regimens and 224 to the control tacrolimus/methotrexate regimen. In the experimental arms, 92 patients received mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide; 89 patients received tacrolimus/methotrexate/maraviroc, and 92 patients received tacrolimus/methotrexate/bortezomib.
“According to predetermined parameters for success, tacrolimus/mycophenolate mofetil/cyclophosphamide was superior to control in GRFS, severe acute GVHD, chronic GVHD requiring immunosuppression, and GVHD-free survival, without a negative impact on treatment-related mortality, relapse/progression, overall survival or disease-free survival,” Dr. Bolaños-Meade said.
Patients could be included in the study if they had acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome; patients with these diagnoses could have no circulating blasts and had to have less than 10% blasts in bone marrow. Patients with chronic lymphocytic leukemia and lymphoma with sensitive disease at the time of transplant were also eligible. All patients received peripheral blood stem cells, and underwent reduced intensity conditioning.
Permissible conditioning regimens included fludarabine/busulfan dosed at 8 mg/kg or less, fludarabine/cyclophosphamide with or without total body irradiation (TBI), fludarabine/TBI at 200 cGy, or fludarabine/melphalan dosed at less than 150 mg/m2 of body surface area. Alemtuzumab and anti-thymocyte globulin were not permitted.
Patients had to have a cardiac ejection fraction greater than 40%. For inclusion, patients had to have estimated creatinine clearance greater than 40 mL/min, bilirubin less than two times the upper limit of normal, and ALT/AST less than 2.5 times the upper limit of normal. Inclusion criteria also required adequate pulmonary function, defined as hemoglobin-corrected diffused capacity of carbon monoxide of at least 40% and forced expiratory volume in one second of 50% or greater.
Patients’ donors had to be either siblings, or 7/8 or 8/8 human leukocyte antigen-matched unrelated donors.
The patients receiving tacrolimus/methotrexate who served as controls were also collected prospectively, from centers that were not participating in the three-arm clinical trial. These patients also received reduced intensity conditioning and a peripheral blood stem cell transplant. This arm of the study was run through the Center for International Blood & Marrow Transplant Research. “I want to stress that the entry criteria were the same as for the intervention arms of the study,” Dr. Bolaños-Meade said.
Using a baseline rate of 23% for the GRFS endpoint, Dr. Bolaños-Meade and his collaborators established the size of the intervention and control arm so that the study would have 86%-88% power to detect a 20% improvement in the rate of GRFS over the contemporary control GVHD prophylaxis.
Across all study arms, patients were a median of 64 years old and most (58%-67%) were men. A little more than half of the patients had a Karnofsky Performance Status of 90%-100%. The Hematopoietic Cell Transplantation–Comorbidity Index was 3 or greater in about 40% of patients in the intervention arms, and in 62% of those in the control arm.
The phase 2 study was not designed to compare each experimental arm against the others, but only to compare each experimental arm to the control, said Dr. Bolaños-Meade, of the department of oncology at Johns Hopkins University, Baltimore.
“The comparisons that were made in this study ... have a limited power to really show superiority,” he said, adding that the National Clinical Trials Network is beginning a phase 3 trial that directly compares posttransplant cyclophosphamide to tacrolimus/methotrexate.
Dr. Bolaños-Meade reported serving on the data safety monitoring board of Incyte.
SOURCE: Bolaños-Meade J et al. 2018 BMT Tandem Meetings, Abstract LBA1.
SALT LAKE CITY – The combination of mycophenolate mofetil, tacrolimus, and posttransplant cyclophosphamide outperformed other prophylaxis regimens at reducing graft versus host disease with relapse-free survival in a multicenter trial.
The trial’s primary aim was to compare rates of post–hematopoietic stem cell transplant GVHD-free and relapse-free survival (GRFS) in the three study arms, compared with the tacrolimus/methotrexate group, who were receiving a “contemporary control,” Javier Bolaños-Meade, MD, said during a late-breaking abstract session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide group had a hazard ratio of 0.72 for reaching the primary endpoint – GRFS (95% confidence interval, 0.55-0.94; P = .04), compared with patients receiving the control regimen. In the study, GRFS was defined as the amount of time elapsed between transplant and any of: grade III-IV acute GVHD, chronic GVHD severe enough to require systemic therapy, disease relapse or progression, or death. Grade III-IV acute GVHD and GVHD survival were superior with mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide, compared with the control (P = .006 and .01, respectively).
The phase 2 trial enrolled adults aged 18-75 years who had a malignant disease and a matched donor, and were slated to receive reduced intensity conditioning. The study randomized patients 1:1:1 to one of three experimental regimens and 224 to the control tacrolimus/methotrexate regimen. In the experimental arms, 92 patients received mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide; 89 patients received tacrolimus/methotrexate/maraviroc, and 92 patients received tacrolimus/methotrexate/bortezomib.
“According to predetermined parameters for success, tacrolimus/mycophenolate mofetil/cyclophosphamide was superior to control in GRFS, severe acute GVHD, chronic GVHD requiring immunosuppression, and GVHD-free survival, without a negative impact on treatment-related mortality, relapse/progression, overall survival or disease-free survival,” Dr. Bolaños-Meade said.
Patients could be included in the study if they had acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome; patients with these diagnoses could have no circulating blasts and had to have less than 10% blasts in bone marrow. Patients with chronic lymphocytic leukemia and lymphoma with sensitive disease at the time of transplant were also eligible. All patients received peripheral blood stem cells, and underwent reduced intensity conditioning.
Permissible conditioning regimens included fludarabine/busulfan dosed at 8 mg/kg or less, fludarabine/cyclophosphamide with or without total body irradiation (TBI), fludarabine/TBI at 200 cGy, or fludarabine/melphalan dosed at less than 150 mg/m2 of body surface area. Alemtuzumab and anti-thymocyte globulin were not permitted.
Patients had to have a cardiac ejection fraction greater than 40%. For inclusion, patients had to have estimated creatinine clearance greater than 40 mL/min, bilirubin less than two times the upper limit of normal, and ALT/AST less than 2.5 times the upper limit of normal. Inclusion criteria also required adequate pulmonary function, defined as hemoglobin-corrected diffused capacity of carbon monoxide of at least 40% and forced expiratory volume in one second of 50% or greater.
Patients’ donors had to be either siblings, or 7/8 or 8/8 human leukocyte antigen-matched unrelated donors.
The patients receiving tacrolimus/methotrexate who served as controls were also collected prospectively, from centers that were not participating in the three-arm clinical trial. These patients also received reduced intensity conditioning and a peripheral blood stem cell transplant. This arm of the study was run through the Center for International Blood & Marrow Transplant Research. “I want to stress that the entry criteria were the same as for the intervention arms of the study,” Dr. Bolaños-Meade said.
Using a baseline rate of 23% for the GRFS endpoint, Dr. Bolaños-Meade and his collaborators established the size of the intervention and control arm so that the study would have 86%-88% power to detect a 20% improvement in the rate of GRFS over the contemporary control GVHD prophylaxis.
Across all study arms, patients were a median of 64 years old and most (58%-67%) were men. A little more than half of the patients had a Karnofsky Performance Status of 90%-100%. The Hematopoietic Cell Transplantation–Comorbidity Index was 3 or greater in about 40% of patients in the intervention arms, and in 62% of those in the control arm.
The phase 2 study was not designed to compare each experimental arm against the others, but only to compare each experimental arm to the control, said Dr. Bolaños-Meade, of the department of oncology at Johns Hopkins University, Baltimore.
“The comparisons that were made in this study ... have a limited power to really show superiority,” he said, adding that the National Clinical Trials Network is beginning a phase 3 trial that directly compares posttransplant cyclophosphamide to tacrolimus/methotrexate.
Dr. Bolaños-Meade reported serving on the data safety monitoring board of Incyte.
SOURCE: Bolaños-Meade J et al. 2018 BMT Tandem Meetings, Abstract LBA1.
SALT LAKE CITY – The combination of mycophenolate mofetil, tacrolimus, and posttransplant cyclophosphamide outperformed other prophylaxis regimens at reducing graft versus host disease with relapse-free survival in a multicenter trial.
The trial’s primary aim was to compare rates of post–hematopoietic stem cell transplant GVHD-free and relapse-free survival (GRFS) in the three study arms, compared with the tacrolimus/methotrexate group, who were receiving a “contemporary control,” Javier Bolaños-Meade, MD, said during a late-breaking abstract session of the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide group had a hazard ratio of 0.72 for reaching the primary endpoint – GRFS (95% confidence interval, 0.55-0.94; P = .04), compared with patients receiving the control regimen. In the study, GRFS was defined as the amount of time elapsed between transplant and any of: grade III-IV acute GVHD, chronic GVHD severe enough to require systemic therapy, disease relapse or progression, or death. Grade III-IV acute GVHD and GVHD survival were superior with mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide, compared with the control (P = .006 and .01, respectively).
The phase 2 trial enrolled adults aged 18-75 years who had a malignant disease and a matched donor, and were slated to receive reduced intensity conditioning. The study randomized patients 1:1:1 to one of three experimental regimens and 224 to the control tacrolimus/methotrexate regimen. In the experimental arms, 92 patients received mycophenolate mofetil/tacrolimus/posttransplant cyclophosphamide; 89 patients received tacrolimus/methotrexate/maraviroc, and 92 patients received tacrolimus/methotrexate/bortezomib.
“According to predetermined parameters for success, tacrolimus/mycophenolate mofetil/cyclophosphamide was superior to control in GRFS, severe acute GVHD, chronic GVHD requiring immunosuppression, and GVHD-free survival, without a negative impact on treatment-related mortality, relapse/progression, overall survival or disease-free survival,” Dr. Bolaños-Meade said.
Patients could be included in the study if they had acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome; patients with these diagnoses could have no circulating blasts and had to have less than 10% blasts in bone marrow. Patients with chronic lymphocytic leukemia and lymphoma with sensitive disease at the time of transplant were also eligible. All patients received peripheral blood stem cells, and underwent reduced intensity conditioning.
Permissible conditioning regimens included fludarabine/busulfan dosed at 8 mg/kg or less, fludarabine/cyclophosphamide with or without total body irradiation (TBI), fludarabine/TBI at 200 cGy, or fludarabine/melphalan dosed at less than 150 mg/m2 of body surface area. Alemtuzumab and anti-thymocyte globulin were not permitted.
Patients had to have a cardiac ejection fraction greater than 40%. For inclusion, patients had to have estimated creatinine clearance greater than 40 mL/min, bilirubin less than two times the upper limit of normal, and ALT/AST less than 2.5 times the upper limit of normal. Inclusion criteria also required adequate pulmonary function, defined as hemoglobin-corrected diffused capacity of carbon monoxide of at least 40% and forced expiratory volume in one second of 50% or greater.
Patients’ donors had to be either siblings, or 7/8 or 8/8 human leukocyte antigen-matched unrelated donors.
The patients receiving tacrolimus/methotrexate who served as controls were also collected prospectively, from centers that were not participating in the three-arm clinical trial. These patients also received reduced intensity conditioning and a peripheral blood stem cell transplant. This arm of the study was run through the Center for International Blood & Marrow Transplant Research. “I want to stress that the entry criteria were the same as for the intervention arms of the study,” Dr. Bolaños-Meade said.
Using a baseline rate of 23% for the GRFS endpoint, Dr. Bolaños-Meade and his collaborators established the size of the intervention and control arm so that the study would have 86%-88% power to detect a 20% improvement in the rate of GRFS over the contemporary control GVHD prophylaxis.
Across all study arms, patients were a median of 64 years old and most (58%-67%) were men. A little more than half of the patients had a Karnofsky Performance Status of 90%-100%. The Hematopoietic Cell Transplantation–Comorbidity Index was 3 or greater in about 40% of patients in the intervention arms, and in 62% of those in the control arm.
The phase 2 study was not designed to compare each experimental arm against the others, but only to compare each experimental arm to the control, said Dr. Bolaños-Meade, of the department of oncology at Johns Hopkins University, Baltimore.
“The comparisons that were made in this study ... have a limited power to really show superiority,” he said, adding that the National Clinical Trials Network is beginning a phase 3 trial that directly compares posttransplant cyclophosphamide to tacrolimus/methotrexate.
Dr. Bolaños-Meade reported serving on the data safety monitoring board of Incyte.
SOURCE: Bolaños-Meade J et al. 2018 BMT Tandem Meetings, Abstract LBA1.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: The hazard ratio for GVHD-free and relapse-free survival was 0.72 for those receiving cyclophosphamide, compared with controls (P = .04).
Study details: Randomized, controlled trial of 497 patients receiving one of three intervention arm posttransplant regimens for GVHD prophylaxis, or a control regimen of tacrolimus and methotrexate.
Disclosures: Dr. Bolaños-Meade reported serving on the data safety monitoring board of Incyte.
Source: Bolaños-Meade J et al. 2018 BMT Tandem Meetings, Abstract LB1.
Ibrutinib preserves immune memory while fighting cGVHD
SALT LAKE CITY – Ibrutinib’s effectiveness in inhibiting chronic graft versus host disease (cGVHD) may hinge in part on inhibition of pre–germinal center B cells and follicular helper cells, according to a new analysis of clinical trial data.
The analysis also showed that ibrutinib preserved immune memory and type 1 T-helper cells.
Bita Sahaf, PhD, presented results of a “comprehensive and high dimensional proteomic approach” to data from 42 patients who were enrolled in a phase 1/2 clinical trial of ibrutinib for cGVHD (NCT02195869).
In that study, 80% of patients who had two or more organs affected by cGVHD responded in at least two organs; overall, two-thirds of patients had a complete or partial response with ibrutinib. The highest response rates were seen in disease affecting the skin, mouth, and gastrointestinal tract.
The new analysis used blood samples from trial participants collected before and during ibrutinib therapy to look for soluble plasma factors known to be related to inflammation, fibrosis, and cGVHD.
“A heat map of cytokines, chemokines, and factors associated with fibrosis shows a significant decrease following ibrutinib treatment,” Dr. Sahaf said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
In addition, inflammatory gene expression was reduced with ibrutinib use, with reductions in the chemokines nuclear factor kappa-B-1, CXCL10, CCL7, and CCL3 dropping by 2.6-fold, 2.3-fold, 25-fold, and 1.8-fold, respectively, after 3 months of ibrutinib therapy, Dr. Sahaf and her colleagues reported.
The investigators used several different techniques to tease apart the mechanisms behind ibrutinib’s effectiveness. Immunophenotyping was accomplished with cytometry by time of flight (CyTOF), a technique that uses transition element isotopes to tag antibodies, which are then analyzed on a cell-by-cell basis by a time-of-flight mass spectrometer.
Ibrutinib inhibits CD19+CD38+CD27+IgD+ pre–germinal center B cells as well as pathogenic CD4+ T follicular helper cells, both implicated in cGVHD, the investigators found. However, Th1 T cells were preserved in a patient-by-patient analysis.
The CyTOF technique also allowed a phosphorylation analysis showing ibrutinib’s blocking effect on Bruton’s tyrosine kinase (BTK) as well as IL-2 inducible T-cell kinase (ITK), with subsequent effects on the signaling molecule PLCgamma2. In individual patients, this inhibition was confirmed when BTK-activated B-cell populations were eliminated after ibrutinib therapy, Dr. Sahaf said.
Ibrutinib also decreased phosphorylation of ITK, with subsequent depletion of CD4+, CD185+, and BCL6+ follicular helper T cells, and of other T cell populations still to be characterized. However, neither CD4+Tbet+Th1 cells nor CD4+CD25+CD127dim Treg cells saw depletion.
Importantly, “CD8+ cytotoxic T cells persist,” said Dr. Sahaf. Phosphorylation of ITK, she said, “appears heterogeneous across most T-cell populations.
“These data support the clinical efficacy of ibrutinib in cGVHD and highlight ibrutinib’s multifactorial mechanism of action in this disease,” Dr. Sahaf, of Stanford (Calif.) University, and her collaborators wrote in the abstract accompanying the presentation.
In August 2017, ibrutinib became the first treatment approved by the Food and Drug Administration for cGVHD. It is indicated for adults who have failed at least one other therapy.
“These correlative studies suggest that ibrutinib impacts a number of the immunologic mechanisms underlying the development of chronic graft versus host disease,” Dr. Sahaf said. Taken together, her team’s work has shown a reduction in expression of inflammatory genes and cytokines, and a decrease in plasma levels of chemotactic, inflammatory, and fibrotic cytokines that all have been implicated in cGVHD pathogenesis. The selective inhibition of pre–germinal center B cells and the trend toward reduced follicular helper T cells also plays a role in ibrutinib’s effectiveness, she said.
Ibrutinib’s efficacy in damping down inflammatory pathways that lead to cGVHD does not come at the expense of other immune function, however. Immune memory and Th 1 cells were not affected by ibrutinib administration in the study population, Dr. Sahaf said. Comparing 33 ibrutinib-receiving patients who received intravenous immune globulin with three patients who did not, the investigators saw no differences in relative antibody concentrations for tetanus or Epstein-Barr virus between the two groups.
“Protective antibodies against tetanus and Epstein-Barr virus persist following ibrutinib therapy,” Dr. Sahaf said.
Next up is the iNTEGRATE trial (NCT02959944), a phase 3 study that will test ibrutinib plus prednisone as first-line therapy for cGVHD, Dr. Sahaf said. The research team will continue its extensive proteomics work in this study as well, she said.
Dr. Sahaf reported research funding from Pharmacyclics LLC, an AbbVie company, which markets ibrutinib. She also reported having patent, royalty, or intellectual property arrangements with Stanford University.
SOURCE: Sahaf, B et al. BMT Tandem Meetings, Abstract 2.
SALT LAKE CITY – Ibrutinib’s effectiveness in inhibiting chronic graft versus host disease (cGVHD) may hinge in part on inhibition of pre–germinal center B cells and follicular helper cells, according to a new analysis of clinical trial data.
The analysis also showed that ibrutinib preserved immune memory and type 1 T-helper cells.
Bita Sahaf, PhD, presented results of a “comprehensive and high dimensional proteomic approach” to data from 42 patients who were enrolled in a phase 1/2 clinical trial of ibrutinib for cGVHD (NCT02195869).
In that study, 80% of patients who had two or more organs affected by cGVHD responded in at least two organs; overall, two-thirds of patients had a complete or partial response with ibrutinib. The highest response rates were seen in disease affecting the skin, mouth, and gastrointestinal tract.
The new analysis used blood samples from trial participants collected before and during ibrutinib therapy to look for soluble plasma factors known to be related to inflammation, fibrosis, and cGVHD.
“A heat map of cytokines, chemokines, and factors associated with fibrosis shows a significant decrease following ibrutinib treatment,” Dr. Sahaf said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
In addition, inflammatory gene expression was reduced with ibrutinib use, with reductions in the chemokines nuclear factor kappa-B-1, CXCL10, CCL7, and CCL3 dropping by 2.6-fold, 2.3-fold, 25-fold, and 1.8-fold, respectively, after 3 months of ibrutinib therapy, Dr. Sahaf and her colleagues reported.
The investigators used several different techniques to tease apart the mechanisms behind ibrutinib’s effectiveness. Immunophenotyping was accomplished with cytometry by time of flight (CyTOF), a technique that uses transition element isotopes to tag antibodies, which are then analyzed on a cell-by-cell basis by a time-of-flight mass spectrometer.
Ibrutinib inhibits CD19+CD38+CD27+IgD+ pre–germinal center B cells as well as pathogenic CD4+ T follicular helper cells, both implicated in cGVHD, the investigators found. However, Th1 T cells were preserved in a patient-by-patient analysis.
The CyTOF technique also allowed a phosphorylation analysis showing ibrutinib’s blocking effect on Bruton’s tyrosine kinase (BTK) as well as IL-2 inducible T-cell kinase (ITK), with subsequent effects on the signaling molecule PLCgamma2. In individual patients, this inhibition was confirmed when BTK-activated B-cell populations were eliminated after ibrutinib therapy, Dr. Sahaf said.
Ibrutinib also decreased phosphorylation of ITK, with subsequent depletion of CD4+, CD185+, and BCL6+ follicular helper T cells, and of other T cell populations still to be characterized. However, neither CD4+Tbet+Th1 cells nor CD4+CD25+CD127dim Treg cells saw depletion.
Importantly, “CD8+ cytotoxic T cells persist,” said Dr. Sahaf. Phosphorylation of ITK, she said, “appears heterogeneous across most T-cell populations.
“These data support the clinical efficacy of ibrutinib in cGVHD and highlight ibrutinib’s multifactorial mechanism of action in this disease,” Dr. Sahaf, of Stanford (Calif.) University, and her collaborators wrote in the abstract accompanying the presentation.
In August 2017, ibrutinib became the first treatment approved by the Food and Drug Administration for cGVHD. It is indicated for adults who have failed at least one other therapy.
“These correlative studies suggest that ibrutinib impacts a number of the immunologic mechanisms underlying the development of chronic graft versus host disease,” Dr. Sahaf said. Taken together, her team’s work has shown a reduction in expression of inflammatory genes and cytokines, and a decrease in plasma levels of chemotactic, inflammatory, and fibrotic cytokines that all have been implicated in cGVHD pathogenesis. The selective inhibition of pre–germinal center B cells and the trend toward reduced follicular helper T cells also plays a role in ibrutinib’s effectiveness, she said.
Ibrutinib’s efficacy in damping down inflammatory pathways that lead to cGVHD does not come at the expense of other immune function, however. Immune memory and Th 1 cells were not affected by ibrutinib administration in the study population, Dr. Sahaf said. Comparing 33 ibrutinib-receiving patients who received intravenous immune globulin with three patients who did not, the investigators saw no differences in relative antibody concentrations for tetanus or Epstein-Barr virus between the two groups.
“Protective antibodies against tetanus and Epstein-Barr virus persist following ibrutinib therapy,” Dr. Sahaf said.
Next up is the iNTEGRATE trial (NCT02959944), a phase 3 study that will test ibrutinib plus prednisone as first-line therapy for cGVHD, Dr. Sahaf said. The research team will continue its extensive proteomics work in this study as well, she said.
Dr. Sahaf reported research funding from Pharmacyclics LLC, an AbbVie company, which markets ibrutinib. She also reported having patent, royalty, or intellectual property arrangements with Stanford University.
SOURCE: Sahaf, B et al. BMT Tandem Meetings, Abstract 2.
SALT LAKE CITY – Ibrutinib’s effectiveness in inhibiting chronic graft versus host disease (cGVHD) may hinge in part on inhibition of pre–germinal center B cells and follicular helper cells, according to a new analysis of clinical trial data.
The analysis also showed that ibrutinib preserved immune memory and type 1 T-helper cells.
Bita Sahaf, PhD, presented results of a “comprehensive and high dimensional proteomic approach” to data from 42 patients who were enrolled in a phase 1/2 clinical trial of ibrutinib for cGVHD (NCT02195869).
In that study, 80% of patients who had two or more organs affected by cGVHD responded in at least two organs; overall, two-thirds of patients had a complete or partial response with ibrutinib. The highest response rates were seen in disease affecting the skin, mouth, and gastrointestinal tract.
The new analysis used blood samples from trial participants collected before and during ibrutinib therapy to look for soluble plasma factors known to be related to inflammation, fibrosis, and cGVHD.
“A heat map of cytokines, chemokines, and factors associated with fibrosis shows a significant decrease following ibrutinib treatment,” Dr. Sahaf said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
In addition, inflammatory gene expression was reduced with ibrutinib use, with reductions in the chemokines nuclear factor kappa-B-1, CXCL10, CCL7, and CCL3 dropping by 2.6-fold, 2.3-fold, 25-fold, and 1.8-fold, respectively, after 3 months of ibrutinib therapy, Dr. Sahaf and her colleagues reported.
The investigators used several different techniques to tease apart the mechanisms behind ibrutinib’s effectiveness. Immunophenotyping was accomplished with cytometry by time of flight (CyTOF), a technique that uses transition element isotopes to tag antibodies, which are then analyzed on a cell-by-cell basis by a time-of-flight mass spectrometer.
Ibrutinib inhibits CD19+CD38+CD27+IgD+ pre–germinal center B cells as well as pathogenic CD4+ T follicular helper cells, both implicated in cGVHD, the investigators found. However, Th1 T cells were preserved in a patient-by-patient analysis.
The CyTOF technique also allowed a phosphorylation analysis showing ibrutinib’s blocking effect on Bruton’s tyrosine kinase (BTK) as well as IL-2 inducible T-cell kinase (ITK), with subsequent effects on the signaling molecule PLCgamma2. In individual patients, this inhibition was confirmed when BTK-activated B-cell populations were eliminated after ibrutinib therapy, Dr. Sahaf said.
Ibrutinib also decreased phosphorylation of ITK, with subsequent depletion of CD4+, CD185+, and BCL6+ follicular helper T cells, and of other T cell populations still to be characterized. However, neither CD4+Tbet+Th1 cells nor CD4+CD25+CD127dim Treg cells saw depletion.
Importantly, “CD8+ cytotoxic T cells persist,” said Dr. Sahaf. Phosphorylation of ITK, she said, “appears heterogeneous across most T-cell populations.
“These data support the clinical efficacy of ibrutinib in cGVHD and highlight ibrutinib’s multifactorial mechanism of action in this disease,” Dr. Sahaf, of Stanford (Calif.) University, and her collaborators wrote in the abstract accompanying the presentation.
In August 2017, ibrutinib became the first treatment approved by the Food and Drug Administration for cGVHD. It is indicated for adults who have failed at least one other therapy.
“These correlative studies suggest that ibrutinib impacts a number of the immunologic mechanisms underlying the development of chronic graft versus host disease,” Dr. Sahaf said. Taken together, her team’s work has shown a reduction in expression of inflammatory genes and cytokines, and a decrease in plasma levels of chemotactic, inflammatory, and fibrotic cytokines that all have been implicated in cGVHD pathogenesis. The selective inhibition of pre–germinal center B cells and the trend toward reduced follicular helper T cells also plays a role in ibrutinib’s effectiveness, she said.
Ibrutinib’s efficacy in damping down inflammatory pathways that lead to cGVHD does not come at the expense of other immune function, however. Immune memory and Th 1 cells were not affected by ibrutinib administration in the study population, Dr. Sahaf said. Comparing 33 ibrutinib-receiving patients who received intravenous immune globulin with three patients who did not, the investigators saw no differences in relative antibody concentrations for tetanus or Epstein-Barr virus between the two groups.
“Protective antibodies against tetanus and Epstein-Barr virus persist following ibrutinib therapy,” Dr. Sahaf said.
Next up is the iNTEGRATE trial (NCT02959944), a phase 3 study that will test ibrutinib plus prednisone as first-line therapy for cGVHD, Dr. Sahaf said. The research team will continue its extensive proteomics work in this study as well, she said.
Dr. Sahaf reported research funding from Pharmacyclics LLC, an AbbVie company, which markets ibrutinib. She also reported having patent, royalty, or intellectual property arrangements with Stanford University.
SOURCE: Sahaf, B et al. BMT Tandem Meetings, Abstract 2.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Inflammatory gene expression dropped between 1.8-fold and 25-fold for individual chemokines after ibrutinib treatment.
Study details: Comprehensive proteomics analysis of data from a phase 1/2 clinical trial of ibrutinib as second-line therapy for cGVHD.
Disclosures: The clinical trial was sponsored by Pharmacyclics LLC, an Abbvie company. Dr. Sahaf reported having patent, royalty, or intellectual property arrangements with Stanford University.
Source: Sahaf B et al. 2018 BMT Tandem Meetings. Abstract 2.
Low microbiota diversity linked to poor survival after transplant
SALT LAKE CITY – A multicenter study confirmed that diversity of gut microbiota is associated with better survival after allogeneic hematopoietic cell transplantation (HCT), while low diversity and the predominance of pathogenic bacteria are linked to graft versus host disease (GVHD).
Lower calorie intake and exposure to broad-spectrum antibiotics were both associated with lower diversity, the study found.
“One of the striking findings early on was this association between diversity in the gut and overall survival,” said Jonathan Peled, MD, PhD, noting that his research group also saw that high gut diversity was associated with lower rates of GVHD-related mortality.
“The first question that I want to ask today is ‘Are the patterns of microbiota injury that have been described in single-center studies and their association with clinical outcomes consistent across geography?’” Dr. Peled said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
To answer this, Dr. Peled and his associates at Memorial Sloan Kettering Cancer Center (MSKCC), New York, teamed up with a research group at Duke University, Durham, N.C., and with investigators in Regensburg, Germany. The international group devised a study that would use centralized sequencing and analysis to examine patient fecal samples from all three centers.
In all, 5,310 samples were obtained from 1,034 HCT patients. MSKCC contributed most of the samples (n = 908, 87.8%), with Regensburg contributing 79 (7.6%) and Duke contributing 47 (4.5%).
The most common malignancies treated were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma. The balance of graft sources and conditioning intensity varied between centers, but overall, more than three-quarters of grafts were from peripheral blood stem cells and just over half of patients received myeloablative conditioning.
The centralized microbiota profiling involved extracting bacterial DNA, and then using polymerase chain reaction to amplify 16sRNA for sequencing and subsequent taxonomic identification.
“Samples can be segregated into clusters according to microbiota composition,” said Dr. Peled, a medical oncologist at MSKCC. The investigators used an algorithm called t-distributed stochastic neighbor embedding, or tSNE, to help detect patterns in microbiota composition and diversity before and throughout the HCT process. Visualizations using tSNE allow for two-dimensional representations of complicated associations and interrelatedness in data.
“Color-coded by diversity and time, we see that these early samples tend to be more diverse,” in the tSNE analyses, Dr. Peled said. The later clusters, he said, show evidence of lower diversity and injury.
Individual samples can also be coded in a way that shows clusters by abundance of various bacterial taxa, Dr. Peled said. “The early, diverse cluster tends to be dominated, or filled, by anaerobic commensals such as Firmicutes and Clostridia, which we and others have found are associated with good outcomes after transplant.”
The lower-diversity states seen later, after transplant, tend to be dominated by a variety of pathogenic bacteria, Dr. Peled said. These include Enterococcus and Proteobacteria, a phylum that includes Klebsiella and Escherichia coli species. This predominance has been associated with subsequent bacteremia, he said.
“Patients tend to enter transplant with a relatively diverse flora, and a frequent event in the posttransplant samples is domination by these pathobiomes,” Dr. Peled said. “In some cases, almost the entire composition of the gut is [composed] of a single species.” This loss of diversity and single-species domination was seen across the three geographically diverse research sites, he said.
This decimation of diversity is linked to poor transplant outcomes. In particular, Dr. Peled said, an enterococcus-dominated gut had previously been associated with higher risk for acute GVHD and with gastrointestinal GVHD.
Here, the multisite data showed that at Regensburg, higher enterococcus abundance on days 7-14 post HCT was associated with increased risk of GI GVHD. At MSKCC, enterococcus domination was associated with a hazard ratio of 1.4 for acute GVHD (P = .008). The MSKCC group used data from 503 patients, defining domination as at least 30% relative abundance in any sample from post-HCT days 7-21.
Patients at both MSKCC and Regensburg had a better chance of overall survival if they had high intestinal microbial diversity around the period of neutrophil engraftment, as seen in a sample collected within 7 days of post-HCT day 14. At MSKCC, data for 651 patients showed a statistically significant association (P = .006); this finding was reproduced at Regensburg, which also saw a significant association (P = .015) for the 59 patients studied, Dr. Peled reported.
Increased treatment-related mortality was seen for patients who had low microbial diversity following neutrophil engraftment as well. Of 372 MSKCC patients who had samples available 7-50 days after engraftment, high diversity was associated with better overall survival, and with lower treatment-related mortality (P = .03 for both).
Dr. Peled and his collaborators also divided patients into quartiles by amount of biodiversity. They found that comparing the highest to the lowest biodiversity quartile showed significantly overall survival benefits for the highest-diversity group (P = .007).
The problem starts before transplant, Dr. Peled explained. The researchers found that compared with healthy controls at MSKCC and data from the Human Microbiome Project, HCT patients entered their transplant with significantly less gut biodiversity.
The second question to be addressed is “What are the key environmental determinants of intestinal microbiota composition?” said Dr. Peled.
“Peri-HCT exposure to broad-spectrum antibiotics is associated with lower intestinal microbial diversity,” he said. For 5,936 samples taken from 976 patients receiving allogeneic HCT, the most significant difference in diversity between those with and without broad-spectrum antibiotic exposure was seen at day 15 post transplant (P = .008).
Higher calorie intake was also associated with greater diversity (P less than .001). Higher dietary fiber intake was associated with higher abundance of Blautia, a genus considered to be a healthy commensal microorganism, Dr. Peled said.
“Conditioning intensity is associated with the magnitude of diversity loss, and with distinct microbiome configurations,” said Dr. Peled. Using 4,311 samples from 908 patients, a myeloablative conditioning regimen (n = 508) was associated with significantly less diversity when compared with reduced intensity (n = 316) and nonmyeloablative regimens (n = 84; P =.002 and P less than .001, respectively).
To answer a third question – What is the natural history of recovery from microbiota injury after HCT? – the investigators looked at trends over time for 28 allogeneic HCT recipients. With a total of 294 samples for analysis, Dr. Peled and his group found that “diversity increases, but often to a configuration distinct from the pre-HCT state.” It took some patients nearly a year to return to their pretransplant level of diversity.
Patients in the subset of those who go on to develop lower gastrointestinal GVHD have an intestinal microbiota composition that is distinct from those patients whose GVHD exclusively involved the upper gastrointestinal tract, the skin, or the liver (P = .019), Dr. Peled said.
He and his team are currently enrolling patients for a phase 2 randomized clinical trial (NCT03078010) that will explore strategies to deescalate the use of broad-spectrum antibiotics for febrile neutropenia in patients with allogeneic HCT. The trial will randomize patients to receive either piperacillin-tazobactam, the current standard of care at MSKCC, or cefepime with deescalation to aztreonam with vancomycin, the microbiota-sparing strategy. The trial will examine the abundance of Clostridiales and Blautia species, gut biodiversity, the rate of GVHD, bacteremia, and survival rates.
The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics
SOURCE: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
SALT LAKE CITY – A multicenter study confirmed that diversity of gut microbiota is associated with better survival after allogeneic hematopoietic cell transplantation (HCT), while low diversity and the predominance of pathogenic bacteria are linked to graft versus host disease (GVHD).
Lower calorie intake and exposure to broad-spectrum antibiotics were both associated with lower diversity, the study found.
“One of the striking findings early on was this association between diversity in the gut and overall survival,” said Jonathan Peled, MD, PhD, noting that his research group also saw that high gut diversity was associated with lower rates of GVHD-related mortality.
“The first question that I want to ask today is ‘Are the patterns of microbiota injury that have been described in single-center studies and their association with clinical outcomes consistent across geography?’” Dr. Peled said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
To answer this, Dr. Peled and his associates at Memorial Sloan Kettering Cancer Center (MSKCC), New York, teamed up with a research group at Duke University, Durham, N.C., and with investigators in Regensburg, Germany. The international group devised a study that would use centralized sequencing and analysis to examine patient fecal samples from all three centers.
In all, 5,310 samples were obtained from 1,034 HCT patients. MSKCC contributed most of the samples (n = 908, 87.8%), with Regensburg contributing 79 (7.6%) and Duke contributing 47 (4.5%).
The most common malignancies treated were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma. The balance of graft sources and conditioning intensity varied between centers, but overall, more than three-quarters of grafts were from peripheral blood stem cells and just over half of patients received myeloablative conditioning.
The centralized microbiota profiling involved extracting bacterial DNA, and then using polymerase chain reaction to amplify 16sRNA for sequencing and subsequent taxonomic identification.
“Samples can be segregated into clusters according to microbiota composition,” said Dr. Peled, a medical oncologist at MSKCC. The investigators used an algorithm called t-distributed stochastic neighbor embedding, or tSNE, to help detect patterns in microbiota composition and diversity before and throughout the HCT process. Visualizations using tSNE allow for two-dimensional representations of complicated associations and interrelatedness in data.
“Color-coded by diversity and time, we see that these early samples tend to be more diverse,” in the tSNE analyses, Dr. Peled said. The later clusters, he said, show evidence of lower diversity and injury.
Individual samples can also be coded in a way that shows clusters by abundance of various bacterial taxa, Dr. Peled said. “The early, diverse cluster tends to be dominated, or filled, by anaerobic commensals such as Firmicutes and Clostridia, which we and others have found are associated with good outcomes after transplant.”
The lower-diversity states seen later, after transplant, tend to be dominated by a variety of pathogenic bacteria, Dr. Peled said. These include Enterococcus and Proteobacteria, a phylum that includes Klebsiella and Escherichia coli species. This predominance has been associated with subsequent bacteremia, he said.
“Patients tend to enter transplant with a relatively diverse flora, and a frequent event in the posttransplant samples is domination by these pathobiomes,” Dr. Peled said. “In some cases, almost the entire composition of the gut is [composed] of a single species.” This loss of diversity and single-species domination was seen across the three geographically diverse research sites, he said.
This decimation of diversity is linked to poor transplant outcomes. In particular, Dr. Peled said, an enterococcus-dominated gut had previously been associated with higher risk for acute GVHD and with gastrointestinal GVHD.
Here, the multisite data showed that at Regensburg, higher enterococcus abundance on days 7-14 post HCT was associated with increased risk of GI GVHD. At MSKCC, enterococcus domination was associated with a hazard ratio of 1.4 for acute GVHD (P = .008). The MSKCC group used data from 503 patients, defining domination as at least 30% relative abundance in any sample from post-HCT days 7-21.
Patients at both MSKCC and Regensburg had a better chance of overall survival if they had high intestinal microbial diversity around the period of neutrophil engraftment, as seen in a sample collected within 7 days of post-HCT day 14. At MSKCC, data for 651 patients showed a statistically significant association (P = .006); this finding was reproduced at Regensburg, which also saw a significant association (P = .015) for the 59 patients studied, Dr. Peled reported.
Increased treatment-related mortality was seen for patients who had low microbial diversity following neutrophil engraftment as well. Of 372 MSKCC patients who had samples available 7-50 days after engraftment, high diversity was associated with better overall survival, and with lower treatment-related mortality (P = .03 for both).
Dr. Peled and his collaborators also divided patients into quartiles by amount of biodiversity. They found that comparing the highest to the lowest biodiversity quartile showed significantly overall survival benefits for the highest-diversity group (P = .007).
The problem starts before transplant, Dr. Peled explained. The researchers found that compared with healthy controls at MSKCC and data from the Human Microbiome Project, HCT patients entered their transplant with significantly less gut biodiversity.
The second question to be addressed is “What are the key environmental determinants of intestinal microbiota composition?” said Dr. Peled.
“Peri-HCT exposure to broad-spectrum antibiotics is associated with lower intestinal microbial diversity,” he said. For 5,936 samples taken from 976 patients receiving allogeneic HCT, the most significant difference in diversity between those with and without broad-spectrum antibiotic exposure was seen at day 15 post transplant (P = .008).
Higher calorie intake was also associated with greater diversity (P less than .001). Higher dietary fiber intake was associated with higher abundance of Blautia, a genus considered to be a healthy commensal microorganism, Dr. Peled said.
“Conditioning intensity is associated with the magnitude of diversity loss, and with distinct microbiome configurations,” said Dr. Peled. Using 4,311 samples from 908 patients, a myeloablative conditioning regimen (n = 508) was associated with significantly less diversity when compared with reduced intensity (n = 316) and nonmyeloablative regimens (n = 84; P =.002 and P less than .001, respectively).
To answer a third question – What is the natural history of recovery from microbiota injury after HCT? – the investigators looked at trends over time for 28 allogeneic HCT recipients. With a total of 294 samples for analysis, Dr. Peled and his group found that “diversity increases, but often to a configuration distinct from the pre-HCT state.” It took some patients nearly a year to return to their pretransplant level of diversity.
Patients in the subset of those who go on to develop lower gastrointestinal GVHD have an intestinal microbiota composition that is distinct from those patients whose GVHD exclusively involved the upper gastrointestinal tract, the skin, or the liver (P = .019), Dr. Peled said.
He and his team are currently enrolling patients for a phase 2 randomized clinical trial (NCT03078010) that will explore strategies to deescalate the use of broad-spectrum antibiotics for febrile neutropenia in patients with allogeneic HCT. The trial will randomize patients to receive either piperacillin-tazobactam, the current standard of care at MSKCC, or cefepime with deescalation to aztreonam with vancomycin, the microbiota-sparing strategy. The trial will examine the abundance of Clostridiales and Blautia species, gut biodiversity, the rate of GVHD, bacteremia, and survival rates.
The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics
SOURCE: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
SALT LAKE CITY – A multicenter study confirmed that diversity of gut microbiota is associated with better survival after allogeneic hematopoietic cell transplantation (HCT), while low diversity and the predominance of pathogenic bacteria are linked to graft versus host disease (GVHD).
Lower calorie intake and exposure to broad-spectrum antibiotics were both associated with lower diversity, the study found.
“One of the striking findings early on was this association between diversity in the gut and overall survival,” said Jonathan Peled, MD, PhD, noting that his research group also saw that high gut diversity was associated with lower rates of GVHD-related mortality.
“The first question that I want to ask today is ‘Are the patterns of microbiota injury that have been described in single-center studies and their association with clinical outcomes consistent across geography?’” Dr. Peled said during a top abstracts session at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
To answer this, Dr. Peled and his associates at Memorial Sloan Kettering Cancer Center (MSKCC), New York, teamed up with a research group at Duke University, Durham, N.C., and with investigators in Regensburg, Germany. The international group devised a study that would use centralized sequencing and analysis to examine patient fecal samples from all three centers.
In all, 5,310 samples were obtained from 1,034 HCT patients. MSKCC contributed most of the samples (n = 908, 87.8%), with Regensburg contributing 79 (7.6%) and Duke contributing 47 (4.5%).
The most common malignancies treated were acute myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma. The balance of graft sources and conditioning intensity varied between centers, but overall, more than three-quarters of grafts were from peripheral blood stem cells and just over half of patients received myeloablative conditioning.
The centralized microbiota profiling involved extracting bacterial DNA, and then using polymerase chain reaction to amplify 16sRNA for sequencing and subsequent taxonomic identification.
“Samples can be segregated into clusters according to microbiota composition,” said Dr. Peled, a medical oncologist at MSKCC. The investigators used an algorithm called t-distributed stochastic neighbor embedding, or tSNE, to help detect patterns in microbiota composition and diversity before and throughout the HCT process. Visualizations using tSNE allow for two-dimensional representations of complicated associations and interrelatedness in data.
“Color-coded by diversity and time, we see that these early samples tend to be more diverse,” in the tSNE analyses, Dr. Peled said. The later clusters, he said, show evidence of lower diversity and injury.
Individual samples can also be coded in a way that shows clusters by abundance of various bacterial taxa, Dr. Peled said. “The early, diverse cluster tends to be dominated, or filled, by anaerobic commensals such as Firmicutes and Clostridia, which we and others have found are associated with good outcomes after transplant.”
The lower-diversity states seen later, after transplant, tend to be dominated by a variety of pathogenic bacteria, Dr. Peled said. These include Enterococcus and Proteobacteria, a phylum that includes Klebsiella and Escherichia coli species. This predominance has been associated with subsequent bacteremia, he said.
“Patients tend to enter transplant with a relatively diverse flora, and a frequent event in the posttransplant samples is domination by these pathobiomes,” Dr. Peled said. “In some cases, almost the entire composition of the gut is [composed] of a single species.” This loss of diversity and single-species domination was seen across the three geographically diverse research sites, he said.
This decimation of diversity is linked to poor transplant outcomes. In particular, Dr. Peled said, an enterococcus-dominated gut had previously been associated with higher risk for acute GVHD and with gastrointestinal GVHD.
Here, the multisite data showed that at Regensburg, higher enterococcus abundance on days 7-14 post HCT was associated with increased risk of GI GVHD. At MSKCC, enterococcus domination was associated with a hazard ratio of 1.4 for acute GVHD (P = .008). The MSKCC group used data from 503 patients, defining domination as at least 30% relative abundance in any sample from post-HCT days 7-21.
Patients at both MSKCC and Regensburg had a better chance of overall survival if they had high intestinal microbial diversity around the period of neutrophil engraftment, as seen in a sample collected within 7 days of post-HCT day 14. At MSKCC, data for 651 patients showed a statistically significant association (P = .006); this finding was reproduced at Regensburg, which also saw a significant association (P = .015) for the 59 patients studied, Dr. Peled reported.
Increased treatment-related mortality was seen for patients who had low microbial diversity following neutrophil engraftment as well. Of 372 MSKCC patients who had samples available 7-50 days after engraftment, high diversity was associated with better overall survival, and with lower treatment-related mortality (P = .03 for both).
Dr. Peled and his collaborators also divided patients into quartiles by amount of biodiversity. They found that comparing the highest to the lowest biodiversity quartile showed significantly overall survival benefits for the highest-diversity group (P = .007).
The problem starts before transplant, Dr. Peled explained. The researchers found that compared with healthy controls at MSKCC and data from the Human Microbiome Project, HCT patients entered their transplant with significantly less gut biodiversity.
The second question to be addressed is “What are the key environmental determinants of intestinal microbiota composition?” said Dr. Peled.
“Peri-HCT exposure to broad-spectrum antibiotics is associated with lower intestinal microbial diversity,” he said. For 5,936 samples taken from 976 patients receiving allogeneic HCT, the most significant difference in diversity between those with and without broad-spectrum antibiotic exposure was seen at day 15 post transplant (P = .008).
Higher calorie intake was also associated with greater diversity (P less than .001). Higher dietary fiber intake was associated with higher abundance of Blautia, a genus considered to be a healthy commensal microorganism, Dr. Peled said.
“Conditioning intensity is associated with the magnitude of diversity loss, and with distinct microbiome configurations,” said Dr. Peled. Using 4,311 samples from 908 patients, a myeloablative conditioning regimen (n = 508) was associated with significantly less diversity when compared with reduced intensity (n = 316) and nonmyeloablative regimens (n = 84; P =.002 and P less than .001, respectively).
To answer a third question – What is the natural history of recovery from microbiota injury after HCT? – the investigators looked at trends over time for 28 allogeneic HCT recipients. With a total of 294 samples for analysis, Dr. Peled and his group found that “diversity increases, but often to a configuration distinct from the pre-HCT state.” It took some patients nearly a year to return to their pretransplant level of diversity.
Patients in the subset of those who go on to develop lower gastrointestinal GVHD have an intestinal microbiota composition that is distinct from those patients whose GVHD exclusively involved the upper gastrointestinal tract, the skin, or the liver (P = .019), Dr. Peled said.
He and his team are currently enrolling patients for a phase 2 randomized clinical trial (NCT03078010) that will explore strategies to deescalate the use of broad-spectrum antibiotics for febrile neutropenia in patients with allogeneic HCT. The trial will randomize patients to receive either piperacillin-tazobactam, the current standard of care at MSKCC, or cefepime with deescalation to aztreonam with vancomycin, the microbiota-sparing strategy. The trial will examine the abundance of Clostridiales and Blautia species, gut biodiversity, the rate of GVHD, bacteremia, and survival rates.
The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics
SOURCE: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: High microbiota diversity post transplant was associated with better overall survival at two sites (P = .006 and P = .015).
Study details: Multicenter study of 5,310 fecal samples obtained from 1,034 hematopoietic cell transplant recipients.
Disclosures: The research presented was funded by the Parker Institute for Cancer Immunotherapy, the Sawiris Foundation, Empire Clinical Research Investigator Program, and Seres Therapeutics. Dr. Peled reported that he has intellectual property rights and research funding through Seres Therapeutics.
Source: Peled J et al. 2018 BMT Tandem Meetings, Abstract 3.
Xenon imaging could detect lung involvement after HSCT
SALT LAKE CITY – Hyperpolarized xenon-129 magnetic resonance imaging, or 129Xe MRI, showed strong promise for revealing early lung ventilation deficits in pediatric hematopoietic stem cell transplant (HSCT) patients in a proof-of-concept study.
The use of hyperpolarized xenon gas in this setting remains investigational, but is emerging as a safe non-ionizing approach for mapping and quantifying regional airway obstruction in the pediatric population. It has been shown to be more sensitive to early disease than the current clinical gold standard of measuring forced expiratory volume in 1 second (FEV1) by spirometry, Laura L. Walkup, PhD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The 129Xe MRI provides regional information that spirometry cannot, allowing for a targeted approach to planned procedures such as bronchoscopy, said Dr. Walkup of Cincinnati Children’s Hospital Medical Center.
“We hypothesized that hyperpolarized 129Xe MRI would be sensitive to lung abnormalities in the pediatric HSCT population,” she said.
Of 13 patients aged 6-13 years (mean, 10 years) who were enrolled in the study and underwent 129XeMRI, 9 also completed spirometry successfully, and the average FEV1 in those patients was 83% of the predicted value.
Ventilation deficits were apparent on the 129Xe MRI imaging in 8 of the 13 subjects and varied in regional distribution. The whole-lung 129Xe ventilation defect percentage for the HSCT group was 14%, which was significantly greater than the approximately 6% ventilation defect percentage in a cohort of age-matched controls, Dr. Walkup said, noting that ventilation deficits were seen in three of four subjects who were unable to complete reliable spirometry.
“So those are lung abnormalities that may have otherwise gone undetected,” she said, adding that hyperpolarized xenon gas also highlighted the wide individual variation in ventilation, even among cases with similar FEV1 percentages.
The findings are notable, because pulmonary complications such as bronchiolitis obliterans are a major source of morbidity and mortality in the pediatric HSCT population, and an accurate and early diagnostic tool identifying the location and severity of suspected obstructive lung pathology following HSCT is desperately needed, she said.
The HSCT patients in the current study included four boys and nine girls. Isotopically-enriched xenon gas (86% 129Xe) was hyperpolarized using a commercial polarizer and images were acquired during a breath hold of up to 16 seconds and up to 1 L of xenon gas. Conventional anatomic MR images also were acquired.
The 129Xe ventilation was quantified using a less than 60% mean whole-lung 129Xe signal threshold, and was compared to FEV1 percentage predicted as measured via spirometry.
The procedure was well tolerated by all patients, Dr. Walkup said, noting that no patients withdrew from the study, and all were able to maintain the required breath hold.
Drops in blood oxygen saturation level did occur, but were transient and resolved within 10-30 seconds of normal breathing. Further, there were no changes in heart rate during imaging, and any side effects related to xenon, such as tingling in extremities, dizziness, or euphoria, were also quickly resolved with normal breathing, she said.
“There were no serious adverse events related to the study ... these results are in good agreement with previously published safety assessments of xenon in kids and in adults, and at our institution we routinely perform xenon imaging in children as young as age 6,” she added.
The findings, which are consistent with those seen in studies of other conditions such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease, suggest that 129Xe MRI is an emerging modality with strong translational potential for detecting early pulmonary involvement following HSCT, she said.
“The real power of the xenon MRI is the spatial information that it provides; we can use that information to plan targeted procedures like bronchoscopy and biopsies ... and since it is non-ionizing, it may be used serially to assess disease progression or response to an intervention,” Dr. Walkup said.
She noted, however, that because it is not yet approved by the Food and Drug Administration, and because it requires specialized expertise and hardware, it is available at only a handful of centers worldwide.
There is a long way to go before the technology will be widely clinically implemented, but work is ongoing at Cincinnati Children’s Hospital to determine how xenon MRI may play a role in pulmonary screening of patients, she said.
Dr. Walkup reported having no financial disclosures.
SOURCE: Walkup L et al. 2018 BMT Tandem Meetings Abstract 56.
SALT LAKE CITY – Hyperpolarized xenon-129 magnetic resonance imaging, or 129Xe MRI, showed strong promise for revealing early lung ventilation deficits in pediatric hematopoietic stem cell transplant (HSCT) patients in a proof-of-concept study.
The use of hyperpolarized xenon gas in this setting remains investigational, but is emerging as a safe non-ionizing approach for mapping and quantifying regional airway obstruction in the pediatric population. It has been shown to be more sensitive to early disease than the current clinical gold standard of measuring forced expiratory volume in 1 second (FEV1) by spirometry, Laura L. Walkup, PhD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The 129Xe MRI provides regional information that spirometry cannot, allowing for a targeted approach to planned procedures such as bronchoscopy, said Dr. Walkup of Cincinnati Children’s Hospital Medical Center.
“We hypothesized that hyperpolarized 129Xe MRI would be sensitive to lung abnormalities in the pediatric HSCT population,” she said.
Of 13 patients aged 6-13 years (mean, 10 years) who were enrolled in the study and underwent 129XeMRI, 9 also completed spirometry successfully, and the average FEV1 in those patients was 83% of the predicted value.
Ventilation deficits were apparent on the 129Xe MRI imaging in 8 of the 13 subjects and varied in regional distribution. The whole-lung 129Xe ventilation defect percentage for the HSCT group was 14%, which was significantly greater than the approximately 6% ventilation defect percentage in a cohort of age-matched controls, Dr. Walkup said, noting that ventilation deficits were seen in three of four subjects who were unable to complete reliable spirometry.
“So those are lung abnormalities that may have otherwise gone undetected,” she said, adding that hyperpolarized xenon gas also highlighted the wide individual variation in ventilation, even among cases with similar FEV1 percentages.
The findings are notable, because pulmonary complications such as bronchiolitis obliterans are a major source of morbidity and mortality in the pediatric HSCT population, and an accurate and early diagnostic tool identifying the location and severity of suspected obstructive lung pathology following HSCT is desperately needed, she said.
The HSCT patients in the current study included four boys and nine girls. Isotopically-enriched xenon gas (86% 129Xe) was hyperpolarized using a commercial polarizer and images were acquired during a breath hold of up to 16 seconds and up to 1 L of xenon gas. Conventional anatomic MR images also were acquired.
The 129Xe ventilation was quantified using a less than 60% mean whole-lung 129Xe signal threshold, and was compared to FEV1 percentage predicted as measured via spirometry.
The procedure was well tolerated by all patients, Dr. Walkup said, noting that no patients withdrew from the study, and all were able to maintain the required breath hold.
Drops in blood oxygen saturation level did occur, but were transient and resolved within 10-30 seconds of normal breathing. Further, there were no changes in heart rate during imaging, and any side effects related to xenon, such as tingling in extremities, dizziness, or euphoria, were also quickly resolved with normal breathing, she said.
“There were no serious adverse events related to the study ... these results are in good agreement with previously published safety assessments of xenon in kids and in adults, and at our institution we routinely perform xenon imaging in children as young as age 6,” she added.
The findings, which are consistent with those seen in studies of other conditions such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease, suggest that 129Xe MRI is an emerging modality with strong translational potential for detecting early pulmonary involvement following HSCT, she said.
“The real power of the xenon MRI is the spatial information that it provides; we can use that information to plan targeted procedures like bronchoscopy and biopsies ... and since it is non-ionizing, it may be used serially to assess disease progression or response to an intervention,” Dr. Walkup said.
She noted, however, that because it is not yet approved by the Food and Drug Administration, and because it requires specialized expertise and hardware, it is available at only a handful of centers worldwide.
There is a long way to go before the technology will be widely clinically implemented, but work is ongoing at Cincinnati Children’s Hospital to determine how xenon MRI may play a role in pulmonary screening of patients, she said.
Dr. Walkup reported having no financial disclosures.
SOURCE: Walkup L et al. 2018 BMT Tandem Meetings Abstract 56.
SALT LAKE CITY – Hyperpolarized xenon-129 magnetic resonance imaging, or 129Xe MRI, showed strong promise for revealing early lung ventilation deficits in pediatric hematopoietic stem cell transplant (HSCT) patients in a proof-of-concept study.
The use of hyperpolarized xenon gas in this setting remains investigational, but is emerging as a safe non-ionizing approach for mapping and quantifying regional airway obstruction in the pediatric population. It has been shown to be more sensitive to early disease than the current clinical gold standard of measuring forced expiratory volume in 1 second (FEV1) by spirometry, Laura L. Walkup, PhD, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
The 129Xe MRI provides regional information that spirometry cannot, allowing for a targeted approach to planned procedures such as bronchoscopy, said Dr. Walkup of Cincinnati Children’s Hospital Medical Center.
“We hypothesized that hyperpolarized 129Xe MRI would be sensitive to lung abnormalities in the pediatric HSCT population,” she said.
Of 13 patients aged 6-13 years (mean, 10 years) who were enrolled in the study and underwent 129XeMRI, 9 also completed spirometry successfully, and the average FEV1 in those patients was 83% of the predicted value.
Ventilation deficits were apparent on the 129Xe MRI imaging in 8 of the 13 subjects and varied in regional distribution. The whole-lung 129Xe ventilation defect percentage for the HSCT group was 14%, which was significantly greater than the approximately 6% ventilation defect percentage in a cohort of age-matched controls, Dr. Walkup said, noting that ventilation deficits were seen in three of four subjects who were unable to complete reliable spirometry.
“So those are lung abnormalities that may have otherwise gone undetected,” she said, adding that hyperpolarized xenon gas also highlighted the wide individual variation in ventilation, even among cases with similar FEV1 percentages.
The findings are notable, because pulmonary complications such as bronchiolitis obliterans are a major source of morbidity and mortality in the pediatric HSCT population, and an accurate and early diagnostic tool identifying the location and severity of suspected obstructive lung pathology following HSCT is desperately needed, she said.
The HSCT patients in the current study included four boys and nine girls. Isotopically-enriched xenon gas (86% 129Xe) was hyperpolarized using a commercial polarizer and images were acquired during a breath hold of up to 16 seconds and up to 1 L of xenon gas. Conventional anatomic MR images also were acquired.
The 129Xe ventilation was quantified using a less than 60% mean whole-lung 129Xe signal threshold, and was compared to FEV1 percentage predicted as measured via spirometry.
The procedure was well tolerated by all patients, Dr. Walkup said, noting that no patients withdrew from the study, and all were able to maintain the required breath hold.
Drops in blood oxygen saturation level did occur, but were transient and resolved within 10-30 seconds of normal breathing. Further, there were no changes in heart rate during imaging, and any side effects related to xenon, such as tingling in extremities, dizziness, or euphoria, were also quickly resolved with normal breathing, she said.
“There were no serious adverse events related to the study ... these results are in good agreement with previously published safety assessments of xenon in kids and in adults, and at our institution we routinely perform xenon imaging in children as young as age 6,” she added.
The findings, which are consistent with those seen in studies of other conditions such as cystic fibrosis, asthma, and chronic obstructive pulmonary disease, suggest that 129Xe MRI is an emerging modality with strong translational potential for detecting early pulmonary involvement following HSCT, she said.
“The real power of the xenon MRI is the spatial information that it provides; we can use that information to plan targeted procedures like bronchoscopy and biopsies ... and since it is non-ionizing, it may be used serially to assess disease progression or response to an intervention,” Dr. Walkup said.
She noted, however, that because it is not yet approved by the Food and Drug Administration, and because it requires specialized expertise and hardware, it is available at only a handful of centers worldwide.
There is a long way to go before the technology will be widely clinically implemented, but work is ongoing at Cincinnati Children’s Hospital to determine how xenon MRI may play a role in pulmonary screening of patients, she said.
Dr. Walkup reported having no financial disclosures.
SOURCE: Walkup L et al. 2018 BMT Tandem Meetings Abstract 56.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point: Hyperpolarized 129Xe MRI shows promise for revealing lung ventilation deficits in pediatric HSCT patients.
Major finding: The whole-lung 129Xe ventilation defect percentage was 14% for HSCT group versus 6% for controls; deficits were seen in three of four subjects who were who were unable to complete reliable spirometry.
Study details: A proof-of-concept study involving 13 children.
Disclosures: Dr. Walkup reported having no financial disclosures.
Source: Walkup L et al. 2018 BMT Tandem Meetings. Abstract 56.
CAR T before transplant yields durable remission in B-cell malignancies
SALT LAKE CITY – Chimeric antigen receptor (CAR) T-cell therapy may be an effective bridge to hematopoietic cell transplant (HCT) for high-risk B-cell malignancies, according to a systematic analysis of patient data from the National Cancer Institute.
Additionally, patients who have received CAR T-cell therapy are likely to enter HCT with a minimal residual disease (MRD)–negative complete response, which raises the possibility of a significantly less intense conditioning regimen that could omit total body irradiation (TBI), Haneen Shalabi, DO, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
“Patients who underwent HCT post–CAR T therapy did not have increased transplant-related morbidity or mortality,” said Dr. Shalabi, a pediatric oncologist in the hematologic diseases division of the National Cancer Institute’s pediatric oncology branch.
The combined approach also overcomes the frequent relapses seen after CAR T-cell therapy in this population. Of the 45 patients who received CAR T-cell therapy and achieved MRD-negative complete response as measured by flow cytometry, 20 did not go on to receive HCT. Of the 20 who didn’t receive HCT, 16 (80%) relapsed; 19 of the 20 (95%) had received prior HCT, said Dr. Shalabi.
However, of the 25 patients who proceeded on to receive HCT, 15 (60%) were in ongoing remission, with a median duration of 35 months (range, 11-55 months). Six patients (24%) experienced transplant-related mortality; four of these patients had no prior HCT. Ten patients (40%) experienced acute graft-versus-host disease (GVHD); two of these patients experienced grade 4 GVHD, and one experienced grade 3 GVHD.
Of the 25 patients who went on to HCT, 19 were receiving their first transplant, with a median time to transplant after CAR T-cell therapy of 57 days. Five patients (20%) had primary refractory disease. Most patients (n = 18; 72%) had TBI-based conditioning prior to their post–CAR T-cell therapy HCT. The median patient age was 15 (range, 5-30) years.
The systematic review included patients from two phase 1 studies; one was of CD19-28z CAR T-cell therapy for children and young adults with B-cell leukemia or lymphoma, and the other was of CD22-41BB CAR T-cell therapy for children and young adults with recurrent or refractory B-cell malignancies expressing CD22.
To weigh the benefit of the combined CAR T-cell therapy/HCT approach, Dr. Shalabi and her colleagues used a competing risk analysis to determine the risk of relapse post-HCT versus the risk of transplant-related mortality. Among patients undergoing their first HCT, the researchers found a 12-month cumulative incidence of relapse of 5.3% with the combined CAR T-cell therapy/HCT approach (95% confidence interval, 0.3%-22.1%). The 24-month cumulative incidence of relapse was 11.3% (95% CI, 1.7%-31.1%).
The analysis also showed the value of next-generation sequencing (NGS). “As we think about utilizing CAR T therapy as a bridge to transplant, we wanted to study the depth of CAR T–induced remission by next-gen sequencing,” Dr. Shalabi said.
Eight patients on the CD22 CAR trial had MRD analyses based on both flow cytometry and NGS. According to flow cytometry, all eight were MRD negative by 1 month; however, according to NGS, two did have detectable disease, which decreased with time. “Next-gen sequencing can identify earlier time points for relapse or ongoing remission” than flow cytometry can, she said.
An additional finding was that two-thirds of the patients who received the CD19/CD28z CAR T cells had no detectable CAR T cells when the pre-HCT conditioning regimen was initiated, said Dr. Shalabi. “CAR persistence – or lack thereof – didn’t impact post-HCT outcomes,” she said, adding that shorter-acting CAR T cells may actually be preferable when HCT is readily available as an option.
“The impact of CAR persistence peritransplant requires further analysis,” Dr. Shalabi said. It’s possible, though, that “consolidative HCT following CAR may synergistically improve event-free and overall survival for this high-risk population.”
Looking forward, Dr. Shalabi and her team are asking bigger questions: “For future directions – and this is a very big question that those in the room would probably like to know – by inducing NGS-negativity, can CAR T therapy allow for HCT conditioning deintensification, potentially reducing the risk of TRM [transplant-related mortality] and long term comorbidities?”
A future trial will explore outcomes for a conditioning regimen that omits TBI for patients who are MRD-negative by NGS, said Dr. Shalabi.
Another direction for her team’s research is to see whether introducing CAR T-cell therapy earlier in a very-high-risk population may improve outcomes; the current study population was heavily pretreated, Dr. Shalabi said.
Dr. Shalabi is employed by the National Cancer Institute. She reported no conflicts of interest.
SOURCE: Shalabi H et al. 2018 BMT Tandem Meetings, Abstract 6.
SALT LAKE CITY – Chimeric antigen receptor (CAR) T-cell therapy may be an effective bridge to hematopoietic cell transplant (HCT) for high-risk B-cell malignancies, according to a systematic analysis of patient data from the National Cancer Institute.
Additionally, patients who have received CAR T-cell therapy are likely to enter HCT with a minimal residual disease (MRD)–negative complete response, which raises the possibility of a significantly less intense conditioning regimen that could omit total body irradiation (TBI), Haneen Shalabi, DO, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
“Patients who underwent HCT post–CAR T therapy did not have increased transplant-related morbidity or mortality,” said Dr. Shalabi, a pediatric oncologist in the hematologic diseases division of the National Cancer Institute’s pediatric oncology branch.
The combined approach also overcomes the frequent relapses seen after CAR T-cell therapy in this population. Of the 45 patients who received CAR T-cell therapy and achieved MRD-negative complete response as measured by flow cytometry, 20 did not go on to receive HCT. Of the 20 who didn’t receive HCT, 16 (80%) relapsed; 19 of the 20 (95%) had received prior HCT, said Dr. Shalabi.
However, of the 25 patients who proceeded on to receive HCT, 15 (60%) were in ongoing remission, with a median duration of 35 months (range, 11-55 months). Six patients (24%) experienced transplant-related mortality; four of these patients had no prior HCT. Ten patients (40%) experienced acute graft-versus-host disease (GVHD); two of these patients experienced grade 4 GVHD, and one experienced grade 3 GVHD.
Of the 25 patients who went on to HCT, 19 were receiving their first transplant, with a median time to transplant after CAR T-cell therapy of 57 days. Five patients (20%) had primary refractory disease. Most patients (n = 18; 72%) had TBI-based conditioning prior to their post–CAR T-cell therapy HCT. The median patient age was 15 (range, 5-30) years.
The systematic review included patients from two phase 1 studies; one was of CD19-28z CAR T-cell therapy for children and young adults with B-cell leukemia or lymphoma, and the other was of CD22-41BB CAR T-cell therapy for children and young adults with recurrent or refractory B-cell malignancies expressing CD22.
To weigh the benefit of the combined CAR T-cell therapy/HCT approach, Dr. Shalabi and her colleagues used a competing risk analysis to determine the risk of relapse post-HCT versus the risk of transplant-related mortality. Among patients undergoing their first HCT, the researchers found a 12-month cumulative incidence of relapse of 5.3% with the combined CAR T-cell therapy/HCT approach (95% confidence interval, 0.3%-22.1%). The 24-month cumulative incidence of relapse was 11.3% (95% CI, 1.7%-31.1%).
The analysis also showed the value of next-generation sequencing (NGS). “As we think about utilizing CAR T therapy as a bridge to transplant, we wanted to study the depth of CAR T–induced remission by next-gen sequencing,” Dr. Shalabi said.
Eight patients on the CD22 CAR trial had MRD analyses based on both flow cytometry and NGS. According to flow cytometry, all eight were MRD negative by 1 month; however, according to NGS, two did have detectable disease, which decreased with time. “Next-gen sequencing can identify earlier time points for relapse or ongoing remission” than flow cytometry can, she said.
An additional finding was that two-thirds of the patients who received the CD19/CD28z CAR T cells had no detectable CAR T cells when the pre-HCT conditioning regimen was initiated, said Dr. Shalabi. “CAR persistence – or lack thereof – didn’t impact post-HCT outcomes,” she said, adding that shorter-acting CAR T cells may actually be preferable when HCT is readily available as an option.
“The impact of CAR persistence peritransplant requires further analysis,” Dr. Shalabi said. It’s possible, though, that “consolidative HCT following CAR may synergistically improve event-free and overall survival for this high-risk population.”
Looking forward, Dr. Shalabi and her team are asking bigger questions: “For future directions – and this is a very big question that those in the room would probably like to know – by inducing NGS-negativity, can CAR T therapy allow for HCT conditioning deintensification, potentially reducing the risk of TRM [transplant-related mortality] and long term comorbidities?”
A future trial will explore outcomes for a conditioning regimen that omits TBI for patients who are MRD-negative by NGS, said Dr. Shalabi.
Another direction for her team’s research is to see whether introducing CAR T-cell therapy earlier in a very-high-risk population may improve outcomes; the current study population was heavily pretreated, Dr. Shalabi said.
Dr. Shalabi is employed by the National Cancer Institute. She reported no conflicts of interest.
SOURCE: Shalabi H et al. 2018 BMT Tandem Meetings, Abstract 6.
SALT LAKE CITY – Chimeric antigen receptor (CAR) T-cell therapy may be an effective bridge to hematopoietic cell transplant (HCT) for high-risk B-cell malignancies, according to a systematic analysis of patient data from the National Cancer Institute.
Additionally, patients who have received CAR T-cell therapy are likely to enter HCT with a minimal residual disease (MRD)–negative complete response, which raises the possibility of a significantly less intense conditioning regimen that could omit total body irradiation (TBI), Haneen Shalabi, DO, said at the combined annual meetings of the Center for International Blood & Marrow Transplant Research and the American Society for Blood and Marrow Transplantation.
“Patients who underwent HCT post–CAR T therapy did not have increased transplant-related morbidity or mortality,” said Dr. Shalabi, a pediatric oncologist in the hematologic diseases division of the National Cancer Institute’s pediatric oncology branch.
The combined approach also overcomes the frequent relapses seen after CAR T-cell therapy in this population. Of the 45 patients who received CAR T-cell therapy and achieved MRD-negative complete response as measured by flow cytometry, 20 did not go on to receive HCT. Of the 20 who didn’t receive HCT, 16 (80%) relapsed; 19 of the 20 (95%) had received prior HCT, said Dr. Shalabi.
However, of the 25 patients who proceeded on to receive HCT, 15 (60%) were in ongoing remission, with a median duration of 35 months (range, 11-55 months). Six patients (24%) experienced transplant-related mortality; four of these patients had no prior HCT. Ten patients (40%) experienced acute graft-versus-host disease (GVHD); two of these patients experienced grade 4 GVHD, and one experienced grade 3 GVHD.
Of the 25 patients who went on to HCT, 19 were receiving their first transplant, with a median time to transplant after CAR T-cell therapy of 57 days. Five patients (20%) had primary refractory disease. Most patients (n = 18; 72%) had TBI-based conditioning prior to their post–CAR T-cell therapy HCT. The median patient age was 15 (range, 5-30) years.
The systematic review included patients from two phase 1 studies; one was of CD19-28z CAR T-cell therapy for children and young adults with B-cell leukemia or lymphoma, and the other was of CD22-41BB CAR T-cell therapy for children and young adults with recurrent or refractory B-cell malignancies expressing CD22.
To weigh the benefit of the combined CAR T-cell therapy/HCT approach, Dr. Shalabi and her colleagues used a competing risk analysis to determine the risk of relapse post-HCT versus the risk of transplant-related mortality. Among patients undergoing their first HCT, the researchers found a 12-month cumulative incidence of relapse of 5.3% with the combined CAR T-cell therapy/HCT approach (95% confidence interval, 0.3%-22.1%). The 24-month cumulative incidence of relapse was 11.3% (95% CI, 1.7%-31.1%).
The analysis also showed the value of next-generation sequencing (NGS). “As we think about utilizing CAR T therapy as a bridge to transplant, we wanted to study the depth of CAR T–induced remission by next-gen sequencing,” Dr. Shalabi said.
Eight patients on the CD22 CAR trial had MRD analyses based on both flow cytometry and NGS. According to flow cytometry, all eight were MRD negative by 1 month; however, according to NGS, two did have detectable disease, which decreased with time. “Next-gen sequencing can identify earlier time points for relapse or ongoing remission” than flow cytometry can, she said.
An additional finding was that two-thirds of the patients who received the CD19/CD28z CAR T cells had no detectable CAR T cells when the pre-HCT conditioning regimen was initiated, said Dr. Shalabi. “CAR persistence – or lack thereof – didn’t impact post-HCT outcomes,” she said, adding that shorter-acting CAR T cells may actually be preferable when HCT is readily available as an option.
“The impact of CAR persistence peritransplant requires further analysis,” Dr. Shalabi said. It’s possible, though, that “consolidative HCT following CAR may synergistically improve event-free and overall survival for this high-risk population.”
Looking forward, Dr. Shalabi and her team are asking bigger questions: “For future directions – and this is a very big question that those in the room would probably like to know – by inducing NGS-negativity, can CAR T therapy allow for HCT conditioning deintensification, potentially reducing the risk of TRM [transplant-related mortality] and long term comorbidities?”
A future trial will explore outcomes for a conditioning regimen that omits TBI for patients who are MRD-negative by NGS, said Dr. Shalabi.
Another direction for her team’s research is to see whether introducing CAR T-cell therapy earlier in a very-high-risk population may improve outcomes; the current study population was heavily pretreated, Dr. Shalabi said.
Dr. Shalabi is employed by the National Cancer Institute. She reported no conflicts of interest.
SOURCE: Shalabi H et al. 2018 BMT Tandem Meetings, Abstract 6.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Of 20 patients receiving CAR T before HCT, 15 (60%) were in ongoing remission of a median 35 months.
Study details: Systematic analysis of 42 patients with B-cell malignancies receiving CAR T-cell therapy at the National Cancer Institute.
Disclosures: The study was conducted at the National Cancer Institute, where Dr. Shalabi is employed.
Source: Shalabi H et al. 2018 BMT Tandem Meetings, Abstract 6.
KD025 shows promise for steroid-dependent cGVHD
SALT LAKE CITY – KD025, an orally available Rho-associated coiled-coil kinase 2–selective inhibitor, is demonstrating encouraging activity and safety in patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2a clinical trial.
Initial results from the ongoing open-label trial known as KD025-208 showed that 11 of 17 patients (65%) and 11 of 16 patients (69%) enrolled in 200-mg daily and 200-mg twice-daily dose cohorts, respectively, had a clinical response with no reported treatment-related serious adverse events at any evaluation time point, Aleksandr Lazaryan, MD, PhD, 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 median duration of treatment in the 200-mg daily group (cohort 1) was 37 weeks, and in the 200-mg twice-daily group (cohort 2) was 28 weeks. At last follow-up, eight patients remained active in each cohort, and these patients had a median treatment duration of 53 and 38 weeks, respectively, he said.
In cohort 1, four patients went off the study because of cGVHD progression, and five withdrew, including two who experienced recurrence of their underlying hematologic malignancy. In cohort 2, 7 of the 16 patients experienced progression of cGVHD, he noted.
Patients in cohorts 1 and 2 had a median age of 52 years and had received at least 2 months of steroid treatment and no more than 3 prior lines of therapy. They were comparable with respect to baseline characteristics, including median time to and duration of GVHD, time from diagnosis to enrollment, median prednisone dose, and median number of prior therapies. They had involvement of various – and often multiple – organ systems: 58% had four or more systems affected at the time of enrollment, and 21% had five or more systems affected.
“This, in a way, reflects a real-life mix of the cGVHD population of patients, with some of those patients having advanced cGVHD,” said Dr. Lazaryan.
Responses were observed across all affected organ systems, with complete responses documented in the upper and lower gastrointestinal tracts. About 75% of patients in cohort 1 who had multiple organ systems involved at enrollment demonstrated responses in at least four organ systems.
Furthermore, the responses were rapid: 68% of responses occurred in the first 8 weeks of treatment and appeared durable, Dr. Lazaryan said, noting that 7 of the 17 patients in cohort 1 had sustained responses for more than 20 weeks, and 3 patients had sustained responses for more than 32 weeks.
“The durability data continue to mature in this trial,” he added.
The adverse events that occurred were consistent with what would be expected for the cGVHD patient population treated with steroids, he said, reporting that no patients discontinued treatment because of infection, no opportunistic or fungal infections have been reported to date, and no treatment-related serious adverse events were reported.
Steroid dose reductions were experienced by 40% and 26% of patients in cohorts 1 and 2, respectively. The dose reductions were achieved in both KD025 responders and nonresponders, he noted.
Overall, four patients (12%) were able to discontinue steroids, and 80% in both cohorts experienced reductions in background tacrolimus.
In addition, up to 65% of patients in cohort 1 achieved a greater than seven point reduction on the Lee cGVHD Symptom Scale, with both responders and nonresponders experiencing improvement on this endpoint.
Chronic GVHD remains a leading cause of post-transplant morbidity and mortality. KD025, which is currently in phase 2 development for inflammatory fibrotic disease, has been shown in preclinical models to down-regulate T helper 17 cells and T follicular helper cells while up-regulating anti-inflammatory regulatory T cells, thereby potentially correcting the immunological imbalance seen in cGVHD, Dr. Lazaryan said.
Analysis is ongoing in this study, including in a third cohort of patients treated with 200 mg of KD025 four times daily, which recently completed accrual. An expansion cohort, at a dose yet to be determined, will include approximately 40 patients, he noted.
The trial is sponsored by Kadmon. Dr. Lazaryan reported advisory board membership and consultancy for GLyPharma Therapeutic.
SOURCE: Lazaryan A et al. 2018 BMT Tandem Meetings, Abstract 38.
SALT LAKE CITY – KD025, an orally available Rho-associated coiled-coil kinase 2–selective inhibitor, is demonstrating encouraging activity and safety in patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2a clinical trial.
Initial results from the ongoing open-label trial known as KD025-208 showed that 11 of 17 patients (65%) and 11 of 16 patients (69%) enrolled in 200-mg daily and 200-mg twice-daily dose cohorts, respectively, had a clinical response with no reported treatment-related serious adverse events at any evaluation time point, Aleksandr Lazaryan, MD, PhD, 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 median duration of treatment in the 200-mg daily group (cohort 1) was 37 weeks, and in the 200-mg twice-daily group (cohort 2) was 28 weeks. At last follow-up, eight patients remained active in each cohort, and these patients had a median treatment duration of 53 and 38 weeks, respectively, he said.
In cohort 1, four patients went off the study because of cGVHD progression, and five withdrew, including two who experienced recurrence of their underlying hematologic malignancy. In cohort 2, 7 of the 16 patients experienced progression of cGVHD, he noted.
Patients in cohorts 1 and 2 had a median age of 52 years and had received at least 2 months of steroid treatment and no more than 3 prior lines of therapy. They were comparable with respect to baseline characteristics, including median time to and duration of GVHD, time from diagnosis to enrollment, median prednisone dose, and median number of prior therapies. They had involvement of various – and often multiple – organ systems: 58% had four or more systems affected at the time of enrollment, and 21% had five or more systems affected.
“This, in a way, reflects a real-life mix of the cGVHD population of patients, with some of those patients having advanced cGVHD,” said Dr. Lazaryan.
Responses were observed across all affected organ systems, with complete responses documented in the upper and lower gastrointestinal tracts. About 75% of patients in cohort 1 who had multiple organ systems involved at enrollment demonstrated responses in at least four organ systems.
Furthermore, the responses were rapid: 68% of responses occurred in the first 8 weeks of treatment and appeared durable, Dr. Lazaryan said, noting that 7 of the 17 patients in cohort 1 had sustained responses for more than 20 weeks, and 3 patients had sustained responses for more than 32 weeks.
“The durability data continue to mature in this trial,” he added.
The adverse events that occurred were consistent with what would be expected for the cGVHD patient population treated with steroids, he said, reporting that no patients discontinued treatment because of infection, no opportunistic or fungal infections have been reported to date, and no treatment-related serious adverse events were reported.
Steroid dose reductions were experienced by 40% and 26% of patients in cohorts 1 and 2, respectively. The dose reductions were achieved in both KD025 responders and nonresponders, he noted.
Overall, four patients (12%) were able to discontinue steroids, and 80% in both cohorts experienced reductions in background tacrolimus.
In addition, up to 65% of patients in cohort 1 achieved a greater than seven point reduction on the Lee cGVHD Symptom Scale, with both responders and nonresponders experiencing improvement on this endpoint.
Chronic GVHD remains a leading cause of post-transplant morbidity and mortality. KD025, which is currently in phase 2 development for inflammatory fibrotic disease, has been shown in preclinical models to down-regulate T helper 17 cells and T follicular helper cells while up-regulating anti-inflammatory regulatory T cells, thereby potentially correcting the immunological imbalance seen in cGVHD, Dr. Lazaryan said.
Analysis is ongoing in this study, including in a third cohort of patients treated with 200 mg of KD025 four times daily, which recently completed accrual. An expansion cohort, at a dose yet to be determined, will include approximately 40 patients, he noted.
The trial is sponsored by Kadmon. Dr. Lazaryan reported advisory board membership and consultancy for GLyPharma Therapeutic.
SOURCE: Lazaryan A et al. 2018 BMT Tandem Meetings, Abstract 38.
SALT LAKE CITY – KD025, an orally available Rho-associated coiled-coil kinase 2–selective inhibitor, is demonstrating encouraging activity and safety in patients with steroid-dependent or refractory chronic graft-versus-host disease (cGVHD) in a phase 2a clinical trial.
Initial results from the ongoing open-label trial known as KD025-208 showed that 11 of 17 patients (65%) and 11 of 16 patients (69%) enrolled in 200-mg daily and 200-mg twice-daily dose cohorts, respectively, had a clinical response with no reported treatment-related serious adverse events at any evaluation time point, Aleksandr Lazaryan, MD, PhD, 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 median duration of treatment in the 200-mg daily group (cohort 1) was 37 weeks, and in the 200-mg twice-daily group (cohort 2) was 28 weeks. At last follow-up, eight patients remained active in each cohort, and these patients had a median treatment duration of 53 and 38 weeks, respectively, he said.
In cohort 1, four patients went off the study because of cGVHD progression, and five withdrew, including two who experienced recurrence of their underlying hematologic malignancy. In cohort 2, 7 of the 16 patients experienced progression of cGVHD, he noted.
Patients in cohorts 1 and 2 had a median age of 52 years and had received at least 2 months of steroid treatment and no more than 3 prior lines of therapy. They were comparable with respect to baseline characteristics, including median time to and duration of GVHD, time from diagnosis to enrollment, median prednisone dose, and median number of prior therapies. They had involvement of various – and often multiple – organ systems: 58% had four or more systems affected at the time of enrollment, and 21% had five or more systems affected.
“This, in a way, reflects a real-life mix of the cGVHD population of patients, with some of those patients having advanced cGVHD,” said Dr. Lazaryan.
Responses were observed across all affected organ systems, with complete responses documented in the upper and lower gastrointestinal tracts. About 75% of patients in cohort 1 who had multiple organ systems involved at enrollment demonstrated responses in at least four organ systems.
Furthermore, the responses were rapid: 68% of responses occurred in the first 8 weeks of treatment and appeared durable, Dr. Lazaryan said, noting that 7 of the 17 patients in cohort 1 had sustained responses for more than 20 weeks, and 3 patients had sustained responses for more than 32 weeks.
“The durability data continue to mature in this trial,” he added.
The adverse events that occurred were consistent with what would be expected for the cGVHD patient population treated with steroids, he said, reporting that no patients discontinued treatment because of infection, no opportunistic or fungal infections have been reported to date, and no treatment-related serious adverse events were reported.
Steroid dose reductions were experienced by 40% and 26% of patients in cohorts 1 and 2, respectively. The dose reductions were achieved in both KD025 responders and nonresponders, he noted.
Overall, four patients (12%) were able to discontinue steroids, and 80% in both cohorts experienced reductions in background tacrolimus.
In addition, up to 65% of patients in cohort 1 achieved a greater than seven point reduction on the Lee cGVHD Symptom Scale, with both responders and nonresponders experiencing improvement on this endpoint.
Chronic GVHD remains a leading cause of post-transplant morbidity and mortality. KD025, which is currently in phase 2 development for inflammatory fibrotic disease, has been shown in preclinical models to down-regulate T helper 17 cells and T follicular helper cells while up-regulating anti-inflammatory regulatory T cells, thereby potentially correcting the immunological imbalance seen in cGVHD, Dr. Lazaryan said.
Analysis is ongoing in this study, including in a third cohort of patients treated with 200 mg of KD025 four times daily, which recently completed accrual. An expansion cohort, at a dose yet to be determined, will include approximately 40 patients, he noted.
The trial is sponsored by Kadmon. Dr. Lazaryan reported advisory board membership and consultancy for GLyPharma Therapeutic.
SOURCE: Lazaryan A et al. 2018 BMT Tandem Meetings, Abstract 38.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Clinical response rates in cohorts 1 and 2 were 65% and 69%, respectively.
Study details: Preliminary findings in 33 patients from a phase 2a trial.
Disclosures: The trial is sponsored by Kadmon. Dr. Lazaryan reported advisory board membership and consultancy for GLyPharma Therapeutic.
Source: Lazaryan A et al. 2018 BMT Tandem Meetings, Abstract 38.
Nonmyeloablative conditioning gets a radiation boost for severe hemoglobinopathies
SALT LAKE CITY – A nonmyeloablative conditioning regimen with a boosted dose of total body irradiation yielded success for a cohort of patients with severe hemoglobinopathy and haploidentical donors.
Of 17 patients with severe sickle cell disease or beta-thalassemia who received allogeneic bone marrow transplants, all but one had successful engraftment, and 13 have achieved full donor chimerism, said Javier Bolaños-Meade, MD.
“Cure of severe hemoglobinopathies is now possible for most patients,” said Dr. Bolaños-Meade. “It should no longer be considered as available to only a fraction of such patients,” such as those who come with a fully-matched donor and those able to tolerate myeloablative conditioning, he said.
Of the patients who received bone marrow transplants, five patients have stopped immunosuppressive therapy, and all patients are alive, having been followed for a median of 15 months (range, 3-34 months).
The rate of graft versus host disease (GVHD) was low: Two patients developed grade 2 acute GVHD, and one patient developed grade 3 acute GVHD; another three patients had mild to moderate chronic GVHD, but all GVHD has resolved, said Dr. Bolaños-Meade.
Historically, the difficulties with transplant in this population were numerous. “No. 1, it’s very difficult to find an HLA-matched donor,” said Dr. Bolaños-Meade. Also, since there’s no target for graft-versus-tumor effect post-transplant, any amount of chronic GVHD is also high on the list of concerns when considering a transplant for hemoglobinopathy.
“The other problem in this group of patients is their ability to tolerate myeloablation,” he said. The accumulated burden of disease, as well as sequelae of transfusion dependence for some, may make a myeloablative regime too risky.
Dr. Bolaños-Meade said that he and his collaborators at Johns Hopkins University, Baltimore, wanted to be able to address all of these concerns in one regimen. “We were trying to work out a system that may be able to solve all the problems – to use nonmyeloablation and to use whatever donor is available.”
His research group had previously shown that nonmyeloablative transplants were well tolerated in patients with sickle cell disease and that haploidentical donors could be used (Blood. 2012 Nov 22;120[22]:4285-91). “However, we had a very high incidence of graft failure,” Dr. Bolaños-Meade said.
A strategy to increase the engraftment rate while still limiting toxicity, he said, would be to increase the dose of total body irradiation used in the conditioning regimen, from 200 to 400 centigray (cGy); this higher dose was incorporated into the study protocol.
Patients were enrolled if they had severe sickle cell disease (SCD; n = 12) or beta-thalassemia (n = 5).
To enroll in the study, SCD patients had to have been hospitalized at least twice a year in the preceding 2 years. The patients with SCD were a median 26 years of age (range, 6-31 years); four were male, and eight were female. Three of the SCD patients were transfusion dependent, and several had such serious complications as osteonecrosis, brain changes seen in medical imaging, and acute coronary syndrome.
The beta-thalassemia patients were a median 7 years of age (range, 6-16 years); all but one were female, and all had been transfusion dependent since infancy.
Bone marrow donors were not all first degree relatives: There were five mothers, four fathers, four brothers, and three sisters, but also an aunt. Two pairs had major ABO incompatibility, and five had minor ABO incompatibility. Ten were ABO compatible.
The conditioning regimen for all patients involved rabbit antithymocyte globulin, fludarabine, and cyclophosphamide, and then total body irradiation given the day before transplant.
After transplant, in addition to standard supportive care, patients received cyclophosphamide on days 3 and 4. Beginning on day 5, patients received mycophenolate mofetil through day 35 and sirolimus for 1 full year after transplant.
The antithymocyte globulin induced sickle cell crises in all SCD patients, and one patient developed sirolimus-induced diabetes. One other patient had a worsening of Meniere disease, and another patient developed BK virus cystitis.
Breaking down outcomes by disease type, Dr. Bolaños-Meade said that the one engraftment failure occurred in an SCD patient. Of the remaining 11 engrafted patients, 9 have full donor chimerism, and all but 1 of the 11 are transfusion independent now. The patient who remains transfusion dependent has mixed chimerism and received bone marrow from a donor with major ABO mismatch. Although one of the five beta-thalassemia patients also has mixed chimerism, all are now transfusion independent.
The boost in hemoglobin post-transplant was relatively modest for the beta-thalassemia group, from a median 9.5 to 10.1 g/dL at the most recent visit. However, the pretransplant levels were boosted by transfusions for all patients in this group, Dr. Bolaños-Meade pointed out.
The SCD patients saw their hemoglobin go from a median 8.65 to 11.4 g/dL (P = .001). Median bilirubin for this group dropped from 2.4 to 0.2 mg/dL (P = .002) with the cessation of sickling-related hemolysis; significant improvements were also seen in absolute reticulocyte counts and lactate dehydrogenase levels.
Dr. Bolaños-Meade reported that he is on the data safety monitoring board of Incyte.
SOURCE: Bolaños-Meade J et al. BMT Tandem Meetings, Abstract LBA-3.
SALT LAKE CITY – A nonmyeloablative conditioning regimen with a boosted dose of total body irradiation yielded success for a cohort of patients with severe hemoglobinopathy and haploidentical donors.
Of 17 patients with severe sickle cell disease or beta-thalassemia who received allogeneic bone marrow transplants, all but one had successful engraftment, and 13 have achieved full donor chimerism, said Javier Bolaños-Meade, MD.
“Cure of severe hemoglobinopathies is now possible for most patients,” said Dr. Bolaños-Meade. “It should no longer be considered as available to only a fraction of such patients,” such as those who come with a fully-matched donor and those able to tolerate myeloablative conditioning, he said.
Of the patients who received bone marrow transplants, five patients have stopped immunosuppressive therapy, and all patients are alive, having been followed for a median of 15 months (range, 3-34 months).
The rate of graft versus host disease (GVHD) was low: Two patients developed grade 2 acute GVHD, and one patient developed grade 3 acute GVHD; another three patients had mild to moderate chronic GVHD, but all GVHD has resolved, said Dr. Bolaños-Meade.
Historically, the difficulties with transplant in this population were numerous. “No. 1, it’s very difficult to find an HLA-matched donor,” said Dr. Bolaños-Meade. Also, since there’s no target for graft-versus-tumor effect post-transplant, any amount of chronic GVHD is also high on the list of concerns when considering a transplant for hemoglobinopathy.
“The other problem in this group of patients is their ability to tolerate myeloablation,” he said. The accumulated burden of disease, as well as sequelae of transfusion dependence for some, may make a myeloablative regime too risky.
Dr. Bolaños-Meade said that he and his collaborators at Johns Hopkins University, Baltimore, wanted to be able to address all of these concerns in one regimen. “We were trying to work out a system that may be able to solve all the problems – to use nonmyeloablation and to use whatever donor is available.”
His research group had previously shown that nonmyeloablative transplants were well tolerated in patients with sickle cell disease and that haploidentical donors could be used (Blood. 2012 Nov 22;120[22]:4285-91). “However, we had a very high incidence of graft failure,” Dr. Bolaños-Meade said.
A strategy to increase the engraftment rate while still limiting toxicity, he said, would be to increase the dose of total body irradiation used in the conditioning regimen, from 200 to 400 centigray (cGy); this higher dose was incorporated into the study protocol.
Patients were enrolled if they had severe sickle cell disease (SCD; n = 12) or beta-thalassemia (n = 5).
To enroll in the study, SCD patients had to have been hospitalized at least twice a year in the preceding 2 years. The patients with SCD were a median 26 years of age (range, 6-31 years); four were male, and eight were female. Three of the SCD patients were transfusion dependent, and several had such serious complications as osteonecrosis, brain changes seen in medical imaging, and acute coronary syndrome.
The beta-thalassemia patients were a median 7 years of age (range, 6-16 years); all but one were female, and all had been transfusion dependent since infancy.
Bone marrow donors were not all first degree relatives: There were five mothers, four fathers, four brothers, and three sisters, but also an aunt. Two pairs had major ABO incompatibility, and five had minor ABO incompatibility. Ten were ABO compatible.
The conditioning regimen for all patients involved rabbit antithymocyte globulin, fludarabine, and cyclophosphamide, and then total body irradiation given the day before transplant.
After transplant, in addition to standard supportive care, patients received cyclophosphamide on days 3 and 4. Beginning on day 5, patients received mycophenolate mofetil through day 35 and sirolimus for 1 full year after transplant.
The antithymocyte globulin induced sickle cell crises in all SCD patients, and one patient developed sirolimus-induced diabetes. One other patient had a worsening of Meniere disease, and another patient developed BK virus cystitis.
Breaking down outcomes by disease type, Dr. Bolaños-Meade said that the one engraftment failure occurred in an SCD patient. Of the remaining 11 engrafted patients, 9 have full donor chimerism, and all but 1 of the 11 are transfusion independent now. The patient who remains transfusion dependent has mixed chimerism and received bone marrow from a donor with major ABO mismatch. Although one of the five beta-thalassemia patients also has mixed chimerism, all are now transfusion independent.
The boost in hemoglobin post-transplant was relatively modest for the beta-thalassemia group, from a median 9.5 to 10.1 g/dL at the most recent visit. However, the pretransplant levels were boosted by transfusions for all patients in this group, Dr. Bolaños-Meade pointed out.
The SCD patients saw their hemoglobin go from a median 8.65 to 11.4 g/dL (P = .001). Median bilirubin for this group dropped from 2.4 to 0.2 mg/dL (P = .002) with the cessation of sickling-related hemolysis; significant improvements were also seen in absolute reticulocyte counts and lactate dehydrogenase levels.
Dr. Bolaños-Meade reported that he is on the data safety monitoring board of Incyte.
SOURCE: Bolaños-Meade J et al. BMT Tandem Meetings, Abstract LBA-3.
SALT LAKE CITY – A nonmyeloablative conditioning regimen with a boosted dose of total body irradiation yielded success for a cohort of patients with severe hemoglobinopathy and haploidentical donors.
Of 17 patients with severe sickle cell disease or beta-thalassemia who received allogeneic bone marrow transplants, all but one had successful engraftment, and 13 have achieved full donor chimerism, said Javier Bolaños-Meade, MD.
“Cure of severe hemoglobinopathies is now possible for most patients,” said Dr. Bolaños-Meade. “It should no longer be considered as available to only a fraction of such patients,” such as those who come with a fully-matched donor and those able to tolerate myeloablative conditioning, he said.
Of the patients who received bone marrow transplants, five patients have stopped immunosuppressive therapy, and all patients are alive, having been followed for a median of 15 months (range, 3-34 months).
The rate of graft versus host disease (GVHD) was low: Two patients developed grade 2 acute GVHD, and one patient developed grade 3 acute GVHD; another three patients had mild to moderate chronic GVHD, but all GVHD has resolved, said Dr. Bolaños-Meade.
Historically, the difficulties with transplant in this population were numerous. “No. 1, it’s very difficult to find an HLA-matched donor,” said Dr. Bolaños-Meade. Also, since there’s no target for graft-versus-tumor effect post-transplant, any amount of chronic GVHD is also high on the list of concerns when considering a transplant for hemoglobinopathy.
“The other problem in this group of patients is their ability to tolerate myeloablation,” he said. The accumulated burden of disease, as well as sequelae of transfusion dependence for some, may make a myeloablative regime too risky.
Dr. Bolaños-Meade said that he and his collaborators at Johns Hopkins University, Baltimore, wanted to be able to address all of these concerns in one regimen. “We were trying to work out a system that may be able to solve all the problems – to use nonmyeloablation and to use whatever donor is available.”
His research group had previously shown that nonmyeloablative transplants were well tolerated in patients with sickle cell disease and that haploidentical donors could be used (Blood. 2012 Nov 22;120[22]:4285-91). “However, we had a very high incidence of graft failure,” Dr. Bolaños-Meade said.
A strategy to increase the engraftment rate while still limiting toxicity, he said, would be to increase the dose of total body irradiation used in the conditioning regimen, from 200 to 400 centigray (cGy); this higher dose was incorporated into the study protocol.
Patients were enrolled if they had severe sickle cell disease (SCD; n = 12) or beta-thalassemia (n = 5).
To enroll in the study, SCD patients had to have been hospitalized at least twice a year in the preceding 2 years. The patients with SCD were a median 26 years of age (range, 6-31 years); four were male, and eight were female. Three of the SCD patients were transfusion dependent, and several had such serious complications as osteonecrosis, brain changes seen in medical imaging, and acute coronary syndrome.
The beta-thalassemia patients were a median 7 years of age (range, 6-16 years); all but one were female, and all had been transfusion dependent since infancy.
Bone marrow donors were not all first degree relatives: There were five mothers, four fathers, four brothers, and three sisters, but also an aunt. Two pairs had major ABO incompatibility, and five had minor ABO incompatibility. Ten were ABO compatible.
The conditioning regimen for all patients involved rabbit antithymocyte globulin, fludarabine, and cyclophosphamide, and then total body irradiation given the day before transplant.
After transplant, in addition to standard supportive care, patients received cyclophosphamide on days 3 and 4. Beginning on day 5, patients received mycophenolate mofetil through day 35 and sirolimus for 1 full year after transplant.
The antithymocyte globulin induced sickle cell crises in all SCD patients, and one patient developed sirolimus-induced diabetes. One other patient had a worsening of Meniere disease, and another patient developed BK virus cystitis.
Breaking down outcomes by disease type, Dr. Bolaños-Meade said that the one engraftment failure occurred in an SCD patient. Of the remaining 11 engrafted patients, 9 have full donor chimerism, and all but 1 of the 11 are transfusion independent now. The patient who remains transfusion dependent has mixed chimerism and received bone marrow from a donor with major ABO mismatch. Although one of the five beta-thalassemia patients also has mixed chimerism, all are now transfusion independent.
The boost in hemoglobin post-transplant was relatively modest for the beta-thalassemia group, from a median 9.5 to 10.1 g/dL at the most recent visit. However, the pretransplant levels were boosted by transfusions for all patients in this group, Dr. Bolaños-Meade pointed out.
The SCD patients saw their hemoglobin go from a median 8.65 to 11.4 g/dL (P = .001). Median bilirubin for this group dropped from 2.4 to 0.2 mg/dL (P = .002) with the cessation of sickling-related hemolysis; significant improvements were also seen in absolute reticulocyte counts and lactate dehydrogenase levels.
Dr. Bolaños-Meade reported that he is on the data safety monitoring board of Incyte.
SOURCE: Bolaños-Meade J et al. BMT Tandem Meetings, Abstract LBA-3.
REPORTING FROM THE 2018 BMT TANDEM MEETINGS
Key clinical point:
Major finding: Of the 17 patients who received haploidentical bone marrow transplant, 13 have achieved full chimerism.
Study details: Report of 17 consecutive patients with severe sickle cell disease or beta-thalassemia who received nonmyeloablative conditioning and bone marrow transplant from haploidentical donors.
Disclosures: Dr. Bolaños-Meade reported no outside sources of funding for the study. He is on the data safety monitoring board of Incyte.
Source: Bolaños-Meade J et al. 2018 BMT Tandem Meetings, Abstract LBA-3.