Abstract
Effective immunosuppressive regimens to prevent the development of graft-versus-host disease (GVHD) are essential to the success of allogeneic hematopoietic cell transplantation (HCT). After revolutionizing haploidentical transplantation, post-transplantation cyclophosphamide (PTCy) is now being evaluated for HCT performed from related and unrelated donors. In this setting, two recent randomized studies have demonstrated lower rates of GVHD and superior GVHD-free, relapse-free survival with PTCy as compared to conventional GVHD prophylaxis. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is currently conducting a large, randomized phase III, multicenter trial (BMT CTN 1703) comparing PTCy/tacrolimus/mycophenolate mofetil to tacrolimus/methotrexate as GVHD prophylaxis regimens in reduced-intensity allogeneic HCT. In this introductory manuscript, we review the ongoing study, highlight its importance to field, and explore the possible implications of results on clinical practice.
Keywords: graft-versus-host disease, prophylaxis, allogeneic hematopoietic cell transplantation
Introduction
The field of hematopoietic cell transplantation (HCT) has benefited from well-conducted, rigorous, multi-center randomized controlled trials. However, the implementation of study results into practice can be unpredictable.1, 2 In 2019, the Executive Committee of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) established the Task Force on Evidence into Practice and charged the Task Force with developing a framework to promote translation of results from BMT CTN clinical trials into clinical practice. This task force brought together diverse stakeholders such as transplant physicians, researchers, medical directors, an implementation scientist and a patient advocate to propose a series of steps to help strengthen the dissemination and implementation efforts in the context of BMT CTN trials. We herein introduce the ongoing study BMT CTN 1703 (NCT0395924)3 and highlight the importance of this study to the field and possible implications for clinical practice.
Background: GVHD prophylaxis
Graft-versus-host disease (GVHD), which occurs when allogeneic donor cells recognize host tissues as foreign, is a major complication after allogeneic HCT.4, 5 Direct end organ damage, as well as secondary risks such as infection, make GVHD a leading cause of morbidity and mortality for transplant recipients. Thus, the success of allogeneic HCT depends on the prevention of GVHD without relapse of underlying disease, which can occur when the alloimmune response is blunted from excessively immunosuppressive GVHD prophylaxis.
After early transplants were performed with methotrexate (MTX) or cyclosporine (CSA) as single-agent GVHD prophylaxis, randomized studies established the combined use of MTX and CSA to be superior to single-agent approaches.6 Tacrolimus (Tac) in combination with MTX became a commonly used regimen after randomized trials in the related and unrelated donor settings showed reductions in acute GVHD compared to CSA/MTX.7, 8 Numerous alternative approaches to GVHD have been investigated, but have failed to significantly improve transplant outcomes.9 Thus, Tac/MTX has remained the standard of care for acute GVHD prophylaxis for many transplant centers, despite its historically limited efficacy, with 40–60% of recipients developing grade II-IV acute GVHD.
More recently, post-transplant cyclophosphamide (PTCy), given in combination with Tac and mycophenolate mofetil (MMF), emerged as a novel approach to GVHD prophylaxis.10 Already adopted as the standard immunosuppressive strategy for haploidentical donor transplantation, two recent randomized trials have investigated the broader application of PTCy to allogeneic HCT (Table 1). In the multicenter, phase II study BMT CTN 1203, 273 subjects were randomized (1:1:1) to one of three GVHD prophylaxis regimens: PTCy/Tac/MMF, Tac/MTX/bortezomib, and Tac/MTX/maraviroc. PTCy/Tac/MMF was the only investigational arm to result in improved GVHD-free, relapse-free survival (GRFS) as compared to a contemporaneous non-randomized prospective cohort of 224 patients receiving Tac/MTX (HR 0.72, 90% CI 0.54–0.94, p=0.04).11 In the multicenter, phase III HOVON-96 trial, 160 subjects were randomized 1:2 between conventional GVHD prophylaxis with CSA/MMF or PTCy/CSA in the setting of HLA-matched related or unrelated allogeneic HCT. PTCy/CSA resulted in lower rates of acute and chronic GVHD without affecting relapse, resulting in an improved one-year estimate of GRFS (45% vs 22%).12 While these studies provide significant support to the expanded use of PTCy-based immunosuppression in allogeneic HCT, further investigation into the effectiveness of this approach compared to the current standard of care is warranted.
Table 1.
Comparative review of recent and ongoing randomized trials of PTCy in GVHD prophylaxis.
| BMT CTN 1203* | HOVON-96 | BMT CTN 1703** | ||
|---|---|---|---|---|
| Study characteristics | ||||
| Study type | Phase II | Phase III | Phase III | |
| Number of subjects | 273 | 160 | 428 | |
| Study arms | PTCy/Tac/MMF, Tac/MTX/bortezomib, or Tac/MTX/maraviroc (non-randomized controls of Tac/MTX) |
PTCy/CSA or CSA/MMF | PTCy/Tac/MMF or Tac/MTX | |
| Donor type | MRD: 36% MUD: 55% MMUD: 9% |
MRD: 31% MUD: 69% |
MRD, MUD or MMUD | |
| Conditioning intensity | RIC: 100% | RIC: 99% MA: 1% |
RIC | |
| Graft source | PBSC: 100% | PBSC: 97% BM: 3% |
PBSC | |
| Study outcomes | ||||
| GRFS at 1 year | PTCy/Tac/MMF: 43% Tac/MTX controls: 34% |
PTCy/CSA: 45% CSA/MMF: 22% |
-- | |
| Grade II-IV Acute GVHD at 6 months |
PTCy/Tac/MMF: 27% Tac/MTX controls: 30% |
PTCy/CSA: 32% CSA/MMF: 48% |
-- | |
| Grade III-IV Acute GVHD at 6 months |
PTCy/Tac/MMF: 2% Tac/MTX controls: 13% |
PTCy/CSA: 6% CSA/MMF: 12% |
-- | |
| Chronic GVHD# | PTCy/Tac/MMF: 22% at 1 year Tac/MTX controls: 37% at 1 year |
PTCy/CSA: 19% at 2 years CSA/MMF: 50% at 2 years |
-- | |
| Relapse or Progression | PTCy/Tac/MMF: 28% at 1 year Tac/MTX controls: 25% at 1 year |
PTCy/CSA: 32% at 3 years CSA/MMF: 26% at 3 years |
-- | |
| Overall Survival | PTCy/Tac/MMF: 71% at 1 year Tac/MTX controls: 71% at 1 year |
PTCy/CSA: 63% at 3 years CSA/MMF: 69% at 3 years |
-- | |
Study outcomes only shown for PTCy/Tac/MMF arm and Tac/MTX controls
Based on study design
Chronic GVHD definitions: BTM CTN 1203: chronic GVHD requiring immunosuppression; HOVON-96: chronic extensive GVHD;
Abbreviations
BM: bone marrow; CSA: cyclosporine A; GRFS: GVHD-free, relapse-free survival; GVHD: graft-versus-host disease; HCT: hematopoietic cell transplantation; MA: myeloablative; MMF: mycophenolate mofetil; MMUD: mismatched unrelated donor; MRD: matched related donor; MTX: methotrexate; MUD: matched unrelated donor; PBSC: peripheral blood stem cells; PTCy: post-transplant cyclophosphamide; RIC: reduced-intensity conditioning; Tac: tacrolimus;
The current study, BMT CTN 1703, aims to determine the effectiveness of PTCy/Tac/MMF in improving outcomes of related and unrelated donor transplants when compared with Tac/MTX, through a multicenter, randomized, Phase III trial.
Primary hypothesis
The primary hypothesis of the current study is that GRFS at 1 year after transplant will be at least 15% greater for subjects who receive PTCy/Tac/MMF for GVHD prophylaxis as compared to subjects who receive Tac/MTX.
Study overview
The study design and objectives are summarized in Figure 1. In addition to the secondary objectives, a companion study, BMT CTN 1801, will collect serial biologic samples from subjects to study changes in the immune repertoire and the intestinal microbiome in transplant recipients and correlate these finding with clinical outcomes.
Figure 1.
BMT CTN 1703 study design and overview.
Abbreviations
GRFS: GVHD-free, relapse-free survival; GVHD: graft-versus-host disease; HCT: hematopoietic cell transplantation; MMF: mycophenolate mofetil; MMUD: mismatched unrelated donor; MRD: matched related donor; MTX: methotrexate; MUD: matched unrelated donor; PBSC: peripheral blood stem cells; PTCy: post-transplant cyclophosphamide; PTLD: post-transplant lymphoproliferative disease; RIC: reduced-intensity conditioning; Tac: tacrolimus;
Eligible patients are adults (≥ 18 years of age) with a diagnosis of a hematologic malignancy. Transplants will be performed using a matched related (6/6 match at HLA-A, -B, and -DRB1) or unrelated (7/8 or 8/8 at HLA-A, -B, -C, and -DRB1) donor. Haploidentical donors are excluded. Patients must have adequate performance status, adequate organ function, and no uncontrolled infections at the time of transplant. Patients will receive a reduced intensity conditioning (fludarabine / busulfan or fludarabine / melphalan) or nonmyeloablative conditioning regimen (fludarabine / cyclophosphamide, fludarabine / total body irradiation or fludarabine / cyclophosphamide / total body irradiation). GVHD prophylaxis regimens are detailed in Figure 1. The planned use of anti-thymocyte globulin or alemtuzumab is excluded for both treatment arms.
The trial is designed to enroll 428 patients (214 per arm). Assuming an accrual period of 36 months and a 12-month follow-up period with a 5% drop-out rate, the sample size can sufficiently maintain a two-sided type I error of 5% while providing 90% statistical power for a two-sided test to detect a HR of 0.66.
The importance of enrollment on this study
As of May 2020, 131 participants (31% of goal) have enrolled on the study. We believe that continued enrollment of this study in the upcoming years is of utmost importance for the HCT community. The current study is the largest randomized study of GVHD prophylaxis ever conducted. It builds upon the promising data generated from BMT CTN 1203 by prospectively randomizing between PTCy/Tac/MMF and Tac/MTX (Table 1). This study also follows the recently presented results of the HOVON-96 study, which demonstrated lower incidences of acute and chronic GVHD and improved GRFS with PTCy as compared to conventional immunosuppression in a Phase III study. In addition to being larger than HOVON-96, (428 subjects vs 160 subjects), the current study also has some key differences that will make the results more applicable to transplant practices in the United States (US). In HOVON-96, the standard immunosuppressive arm consisted of CSA/MMF, which is not commonly administered in US centers based. Additionally, PTCy was combined with CSA, whereas the combination of PTCy/Tac/MMF is more commonly utilized. Despite the limitations of these previous studies, both demonstrated improvement of GRFS with PTCy-based approaches. The current study is large and sufficiently powered to demonstrate a clinically meaningful difference between the investigational arms. For all these reasons, BMT CTN 1703 has the potential to be practice changing. As such, we believe that enrollment on this study should be a high priority for all participating centers across the US.
Implications of possible study results on clinical practice
What are the clinical implications if the study meets its primary outcome?
Meeting the primary endpoint will require clinicians and transplant centers to reconsider the current standard of care for GVHD prophylaxis. A 15% improvement in GRFS will likely compel many to consider using PTCy/Tac/MMF as GVHD prophylaxis in related and unrelated RIC PBSC transplants, even in the absence of an overall survival benefit. However, adoption of this approach will be enhanced if important secondary clinical endpoints, including toxicities, GVHD, relapse, and survival, as well as patient reported outcomes data are supportive of the primary outcome. Furthermore, long-term follow-up of outcomes, beyond the 1-year endpoint of the primary outcome, will support final acceptance of this approach.
What are the clinical implications if the study does not meet its primary outcome?
As GRFS is a composite primary endpoint, careful breakdown of its components will need examination to determine if one study arm results in a significant advantage for one or more clinical components (i.e., acute GVHD, chronic GVHD, relapse, or survival). For example, previous studies have suggested that chronic GVHD is particularly lower with PTCy/Tac/MMF. Given the significant burden on quality of life from chronic GVHD identified in previous BMT CTN studies,13 a clinically meaningful improvement in chronic GVHD may be sufficiently important to change clinical practice despite a negative primary outcome. However, as the power and sample size of the study is for the primary endpoint, more stringent statistical evaluation of secondary endpoints would be required in this scenario.
If no significant differences in the primary or secondary outcomes are identified, we anticipate a possible split decision in regards to the evaluation of study arms: some may argue that Tac/MTX should remain the standard of care as a superior regimen has not been identified, whereas others may argue that PTCy performed as well as the previous standard and should be applied to related and unrelated donors, mirroring the practice in haploidentical transplantation.
How could differences in efficacy across important subgroups impact the interpretation of the study results?
It will also be important to look at subgroup analyses to identify any difference in outcomes in specific patient-, disease- or transplant-related cohorts. For example, if there is a signal about an increased incidence of relapse with PTCy/Tac/MMF in combination with disease type or disease stage, this may be informative about unforeseen risks not previously recognized, thereby influencing uptake of evidence generated by this study. Additional points of interest include evaluating the impact of GVHD prophylaxis according to donor type, as well as evaluating toxicity profiles when used in combination with different conditioning regimens. However, even in this large study, there may be insufficient power to examine differing outcomes within subgroups.
What are the potential limitations of the study that may impact its external validity and thereby influence its adoption?
Clinical trial design limits the number of variables that can be accounted for with randomization. In the current study, randomization is stratified by centers and by the disease risk index (DRI): low, intermediate, or high).14 This potentially allows for differences in clinical variables between the 2 arms, but the large size of this study makes significant differences less likely. There are also clinical variables that may influence outcomes that are not captured in the study, most notably the presence of measurable residual disease and its potential impact on relapse.15
What would be the potential barriers in adopting the study results?
We believe that this study lacks significant infrastructural barriers that would prevent wide adoption of its results. The eligibility criteria for this study are similar to the broad HCT population. Most transplant centers have ample experience using PTCy/Tac/MMF for haploidentical transplantation, and its use does not require additional resource capabilities.
A main limitation in broadly implementing the results of this study may be institutional practices that are not addressed in this study. Examples include the preferred use of alternative graft sources (bone marrow grafts or umbilical cord blood) and other GVHD prophylaxis regimens (the use of anti-thymocyte globulin, T-cell depletion, or the use of Tac/sirolimus). Additionally, the current study does not include subjects receiving myeloblative conditioning, which is preferable to RIC in certain transplant settings.15, 16 The phase III trial BMT CTN 1301, which randomized 345 subjects receiving myeloablative transplants between 3 GVHD prophylaxis regimens (T-cell depletion, PTCy, and Tac/MTX but with BM grafts), has completed accrual and is pending analysis.
Conclusion
BMT CTN 1703 builds upon recent randomized studies showing encouraging results with the use of PTCy-based GVHD prophylaxis in related and unrelated allogeneic PBSC RIC HCT. Continued enrollment may potentially establish a new standard of care in GVHD prevention and improve outcomes for patients. It will not answer every question, but it will be an important step towards defining a preferred GVHD prophylaxis for the patient cohorts enrolled. We encourage that transplant centers consider the clinical implications of potential study results and begin now to address the barriers to achieving adoption of these results. This will ensure the context and culture is primed for uptake once the results are available.
Highlights.
BMT CTN 1703 compares GVHD prophylaxis regimens in reduced-intensity allogeneic HCT.
We highlight this study’s importance and explore the possible implications on clinical practice.
Acknowledgements
We would like to thank Janelle Olson PhD for her support of the BMT CTN Task Force on Evidence into Practice and this manuscript.
Support for this study was provided by grants #U10HL069294 and #U24HL138660 to the Blood and Marrow Transplant Clinical Trials Network from the National Heart, Lung, and Blood Institute and the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Footnotes
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Conflicts of Interest: The authors declare no relevant conflicts of interest
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