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.
 

[email protected]

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.
 

[email protected]

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.
 

[email protected]

SOURCE: Wagner J et al. 2018 BMT Tandem Meetings, Abstract 4.