Optimizing GVHD Prophylaxis: Exploring Intermediate-Dose PTCy in Bone Marrow Transplantation for Older Patients - Insights from Dr. Mustafa Hyder, MD's Study

Dr. Mustafa Hyder spoke about the results from a phase 1/2 trial presented during the 2024 Tandem Meeting.

During the Tandem Meetings I Transplantation & Cellular Therapy Meetings of ASTCT® and CIBMTR®, Dr. Mustafa Hyder from the National Cancer Institute presented the results of a study entitled: Phase I/II Study of Intermediate Dose Post-Transplant Cyclophosphamide after Reduced Intensity Conditioning of HLA-Matched Bone Marrow Transplantation for Older or Infirm Patients.

Can you briefly summarize the rationale behind this study?
Our use of reduced dosing of PTCy is based on pre-clinical work done at the NCI in MHC-haploidentical and MHC-disparate murine HCT models showing that intermediate-dose PTCy (25 mg/kg/day on days +3/+4; ID-PTCy) was the optimal dose in terms of best protection against GVHD, providing superior GVHD control compared with lower or higher doses. As a result, we initiated our first clinical trial using ID-PTCy in the setting of myeloablative HLA-haploidentical bone marrow transplant. Based on the very positive results in that trial, including exceedingly low rates of acute GVHD but also faster engraftment and T-cell reconstitution, less severe and shorter duration mucositis, and less severe BK virus-associated cystitis, we designed this trial for older or infirm patients unable to tolerate myeloablative conditioning for HLA-matched or HLA-mismatched/haploidentical bone marrow transplant.

What was previously known about lower doses of PTCy?
 PTCy 50 mg/kg/day on days +3/+4 was thought superior to 50 mg/kg/day on day +3 only based on results of the first phase II clinical study using PTCy. There have been several reports, mostly small and retrospective, describing the use of lower doses of PTCy ranging from 25 to 40 mg/kg/day on days +3 and +4. Most of these were done using HLA-haploidentical peripheral blood stem cells and several included the use of ATG. Overall, these results have been positive in terms of low toxicity and relatively low rates of clinically significant acute and chronic GVHD.

What was the population studied?
 Patients included in our study had hematologic malignancies with standard indication for transplantation and were either 60 to 85 years of age, or 18 to 59 years, but had co-morbidities that would exclude them from receiving myeloablative conditioning, such as significant organ dysfunction, low performance status, high co-morbidity index, were frail, or had received prior myeloablative conditioning or drugs such as gemtuzumab or inotuzumab that increase the risk for sinusoidal obstruction syndrome. All patients in this specific cohort had available HLA-matched related or unrelated bone marrow donors.

Can you describe the intervention?
 After receiving RIC with fludarabine 30 mg/m2/day (days -6 to -2), cyclophosphamide 14.5 mg/kg/day (days -6 and -5) and TBI 400 cGy in 2x200 cGy fractions on day -1, followed by freshly collected bone marrow on day 0, PTCy was given at a dose of 25 mg/kg/day on days +3 and +4. Importantly, the PTCy administration was given at 72 (+/- 2) hour and 96 (+/- 2) hours after the start of marrow infusion. Adjunct immunosuppression included MMF TID from day +5 to +35 and Sirolimus from day +5 to +60, when it was discontinued without taper.

What was the primary outcome and how was the sample size estimated?
 The primary outcome was the rate of grades III/IV acute GVHD by day +60. The study was based on the Simon optimal two-stage design. Advancing to the second-stage was assessed separately for each cohort and required that at least 5 of the first 6 patients in a given cohort avoid grade III/IV acute GVHD by day +60. Each cohort would enroll up to 20 patients. We have 4 cohorts in the study based on HLA-matched vs. HLA-mismatched/haploidentical and older vs. younger patients. This specific report included both older and younger cohorts of patients receiving HLA-matched bone marrow transplants.

Can you briefly summarize the results?
 So far the results in the HLA-matched cohorts have been very encouraging. 15 patients have been transplanted with a median age of 63 years. Only one patient developed grade II or greater acute GVHD; and another had mild chronic GVHD that resolved fairly quickly — no others have had chronic GVHD. Overall survival and relapse have been better than expected at 83% and 16% at 1 year, despite a high-risk patient population.

How will you move forward after the findings in this study?
 The results using PTCy 25 mg/kg/day on days +3/+4 should be compared in a randomized study against 50 mg/kg/day on days +3/+4 for transplant platforms including RIC and HLA-matched bone marrow grafts. Based on these results and given the low relapse rate, this approach may be extended to a wider pool of patients. We also have an on-going multi-institutional study reducing PTCy dosing in RIC PBSCT, which should be completed to identify optimal dosing for that platform/graft source.

Knowing what you know now, would you change anything in the design of the study?
 Given the really encouraging results with low NRM, relapse, and GVHD, we may have made the study eligibility more inclusive for all patients receiving reduced intensity bone marrow transplant.

How do you envision the role of intermediate doses of PTCy in the future of GVHD prophylaxis?
 High-dose PTCy has negative effects including delaying engraftment and immune recovery, increasing toxicity, and increasing some infectious complications of transplant. We have shown in two studies here at the NCI that lower dosing of PTCy is safe and feasible, at least for bone marrow transplantation. However, the optimal dosing of PTCy needs to be defined across a variety of donor/recipient HLA-matching, graft sources, and conditioning regimens to ensure that the optimal dosing is not platform-specific. If our results hold up in randomized studies, I would expect that intermediate-dose PTCy may become a new standard in the field. We are also collecting cyclophosphamide pharmacokinetic data on all our patients to provide a more comprehensive assessment of PTCy exposure and to relate that with several transplant outcomes. This may eventually lead to personalized PTCy dosing.