A PHASE I/II TRIAL OF INTRAVENOUS AZACITIDINE FOR ACUTE GVHD PROPHYLAXIS IN PATIENTS UNDERGOING MATCHED UNRELATED STEM CELL TRANSPLANTATION: INTERIM PHASE II RESULTS
Author(s): ,
Mark Schroeder
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Jaebok Choi
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Matthew Cooper
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Shedeka Marriott
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Kirsten Gerbic
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Jingxia Liu
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Armin Ghobadi
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Keith Stockerl-Goldstein
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Ravi Vij
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Amanda Cashen
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Abboud Camille
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Meagan Jacoby
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Iskra Pusic
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Rizwan Romee
Affiliations:
Dana Farber Cancer Institute ,Boston,United States
,
Geoffery Uy
Affiliations:
Washington University School of Medicine,Saint Louis,United States
,
Peter Westervelt
Affiliations:
Washington University School of Medicine,Saint Louis,United States
John DiPersio
Affiliations:
Washington University School of Medicine,Saint Louis,United States
EHA Library. Schroeder M. 06/16/18; 215757; PS1471
Mark Schroeder
Mark Schroeder
Contributions
Abstract

Abstract: PS1471

Type: Poster Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00

Location: Poster area

Background

The negative impact of acute graft-versus-host disease (GvHD) on morbidity and mortality after allogeneic transplant is significant; thus, finding a means to harness the beneficial Graft versus tumor effect (GVT) while reducing or eliminating GvHD is a major goal of transplant trials. Alterations in immune subsets present after transplant can work to suppress allo-reactive T-cell responses by increasing regulatory T-cells and suppressing allo-reactive T-cell proliferation. Azacitidine (AZA) treatment in pre-clincal models resulted in an increase in regulatory T-cells, a decrease in allo-reactive T-cell proliferation and prevention of acute GvHD while preserving GVT effects (Choi et al. Blood 2010, Cooper et al. J Immunol 2017). Based on these results a phase I/II study was designed to test the safety and efficacy of AZA administered shortly after transplant for the prevention of acute GvHD and relapse in subjects receiving transplants from matched unrelated stem cell donors.  We are reporting the interim results for Phase II.

Aims
To define the maximum tolerated dose of AZA and the effect on grade II-IV GvHD when given after matched unrelated donor transplant (MUD).

Methods

Patients with hematologic malignancies in remission age 18 – 70 were eligible. Myeloablative or reduced intensity conditioning without antithymocyte globulin was used. All recipients in phase II were required to receive G-CSF mobilized peripheral blood grafts with at least 4 x 106 CD34/kg and have at least 1 x 106 CD34/kg cryopreserved as back up in case of primary graft failure. AZA was administered intravenously on day +7 for five consecutive days and repeated every 28 days for a total of 4 cycles after allogeneic transplant from a 10/10 HLA matched unrelated donor (Figure).  GvHD prophylaxis with mini-methotrexate and tacrolimus was given. Phase I, 3+3 dose escalation design of 4 cohorts (AZA dose levels 15, 30, 37.5, and 45 mg/m2) was used to determine the recommended phase II dose (RP2D). The primary outcome for phase II is the rate of grade II – IV acute GvHD at day 180 after transplant.

Results
The RP2D from phase I was 45 mg/m2 (Schroeder et al. ASH 2015) with one DLT observed secondary to primary graft failure. To date in phase II we have transplanted 35 of 46 planned subjects and all 35 have received study drug. Recipient characteristics include: median age 59 (range 24 – 70); 54% male; diagnoses - AML in CR (22), MDS (13); conditioning - reduced intensity (12), myeloablative (23). Primary graft failure has occurred in one subject in phase II related to HHV6 infection. Median ANC engraftment was 14 days (range excluding case of graft failure 10 - 18 days).  Median platelet engraftment was 19 days (range 10 – NR). To date, the phase II acute GvHD incidence grade II – IV has occurred in 15 (43%) and grade III/IV in 7 (20%).  The majority of cases have responded to steroids with 7 cases of steroid refractory aGvHD. With a median follow up of 248 days (range 27 - 891), 4 subjects have relapsed and 25 (71%) remain alive.  The most common non-hematologic grade 3 or 4 AEs were gastrointestinal toxicity, electrolyte abnormalities, and infections.

Conclusion
In conclusion, AZA can be given safely starting at day +7 after MUD transplant up to a dose of 45mg/m2. Phase II enrollment and follow up is ongoing and will be updated at the meeting. Correlative studies from banked bio-specimens evaluating T-cell subsets and methylation before and after treatment are ongoing.

Session topic: 23. Stem cell transplantation - Clinical

Keyword(s): Allogeneic hematopoietic stem cell transplant, Azacitidine, Graft-versus-host disease (GVHD), Prophylaxis

Abstract: PS1471

Type: Poster Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00

Location: Poster area

Background

The negative impact of acute graft-versus-host disease (GvHD) on morbidity and mortality after allogeneic transplant is significant; thus, finding a means to harness the beneficial Graft versus tumor effect (GVT) while reducing or eliminating GvHD is a major goal of transplant trials. Alterations in immune subsets present after transplant can work to suppress allo-reactive T-cell responses by increasing regulatory T-cells and suppressing allo-reactive T-cell proliferation. Azacitidine (AZA) treatment in pre-clincal models resulted in an increase in regulatory T-cells, a decrease in allo-reactive T-cell proliferation and prevention of acute GvHD while preserving GVT effects (Choi et al. Blood 2010, Cooper et al. J Immunol 2017). Based on these results a phase I/II study was designed to test the safety and efficacy of AZA administered shortly after transplant for the prevention of acute GvHD and relapse in subjects receiving transplants from matched unrelated stem cell donors.  We are reporting the interim results for Phase II.

Aims
To define the maximum tolerated dose of AZA and the effect on grade II-IV GvHD when given after matched unrelated donor transplant (MUD).

Methods

Patients with hematologic malignancies in remission age 18 – 70 were eligible. Myeloablative or reduced intensity conditioning without antithymocyte globulin was used. All recipients in phase II were required to receive G-CSF mobilized peripheral blood grafts with at least 4 x 106 CD34/kg and have at least 1 x 106 CD34/kg cryopreserved as back up in case of primary graft failure. AZA was administered intravenously on day +7 for five consecutive days and repeated every 28 days for a total of 4 cycles after allogeneic transplant from a 10/10 HLA matched unrelated donor (Figure).  GvHD prophylaxis with mini-methotrexate and tacrolimus was given. Phase I, 3+3 dose escalation design of 4 cohorts (AZA dose levels 15, 30, 37.5, and 45 mg/m2) was used to determine the recommended phase II dose (RP2D). The primary outcome for phase II is the rate of grade II – IV acute GvHD at day 180 after transplant.

Results
The RP2D from phase I was 45 mg/m2 (Schroeder et al. ASH 2015) with one DLT observed secondary to primary graft failure. To date in phase II we have transplanted 35 of 46 planned subjects and all 35 have received study drug. Recipient characteristics include: median age 59 (range 24 – 70); 54% male; diagnoses - AML in CR (22), MDS (13); conditioning - reduced intensity (12), myeloablative (23). Primary graft failure has occurred in one subject in phase II related to HHV6 infection. Median ANC engraftment was 14 days (range excluding case of graft failure 10 - 18 days).  Median platelet engraftment was 19 days (range 10 – NR). To date, the phase II acute GvHD incidence grade II – IV has occurred in 15 (43%) and grade III/IV in 7 (20%).  The majority of cases have responded to steroids with 7 cases of steroid refractory aGvHD. With a median follow up of 248 days (range 27 - 891), 4 subjects have relapsed and 25 (71%) remain alive.  The most common non-hematologic grade 3 or 4 AEs were gastrointestinal toxicity, electrolyte abnormalities, and infections.

Conclusion
In conclusion, AZA can be given safely starting at day +7 after MUD transplant up to a dose of 45mg/m2. Phase II enrollment and follow up is ongoing and will be updated at the meeting. Correlative studies from banked bio-specimens evaluating T-cell subsets and methylation before and after treatment are ongoing.

Session topic: 23. Stem cell transplantation - Clinical

Keyword(s): Allogeneic hematopoietic stem cell transplant, Azacitidine, Graft-versus-host disease (GVHD), Prophylaxis

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