Transcript:

Bhagirathbhai Dholaria:  Hi, I am Bhagirathbhai Dholaria. I am an assistant professor in Department of Hematology, Oncology, and Stem Cell Transplant at Vanderbilt University Medical Center in Nashville, Tennessee.

Today, I will be talking about our retrospective study evaluating the outcome of acute lymphoblastic leukemia patients from EBMT database, who underwent haploidentical stem cell transplantation, with post-transplant cyclophosphamide.

This study is basically looking at two different myeloablative conditioning regimen comparing total body irradiation, which is chemotherapy-based conditioning.

Haploidentical stem cell transplant has been increasingly used in patients who specifically do not have full HLA-matched donors. There have been prior study showing a pretty comparable outcome between haploidentical stem cell transplantation and matched unrelated donor stem cell transplantation in patient with acute leukemia.

The original haploidentical with post-transplant cyclophosphamide protocol from John Hopkins University used the reduce intensity conditioning with low dose total body irradiation. However, this is a very effective regimen. High risk leukemia patients reduce intensity conditioning was associated with increased relapse incident.

Subsequently, many groups have reported safety and efficacy of myeloablative conditioning in the platform of haploidentical stem cell transplantation with post-transplant cyclophosphamide. However, ideal myeloablative regimen in the setting of haplo-HCT/PTCy remains to be seen.

We know there are prior studies in ALL patients undergoing match-related transplantation that TBI-based myeloablative conditioning seems to have reduced relapsed incidence and hence better leukemia-free survival compared to chemotherapy-based myeloablative regimen, but that is yet to be proven in haplo-HCT setting.

In our study, we primarily looking at the two different myeloablative condition regimen. TBI-based versus chemotherapy based. We used a large transplant database from European Bone Marrow Transplant.

We selected the adult patients who had transplanted in last eight years from 2010 to 2018, who underwent haplo-HCT with post-transplant cyclophosphamide as their primary GVHD prophylaxis regimen and who had also had diagnosis of acute lymphoblastic leukemia.

We excluded the patient who received any other form of in-vivo or ex-vivo T-cell depletion, so recipient of anti-thymocyte globulin or Campath were excluded from this study. We selected the patient who underwent their first haplo-HCT, of course.

In our final study cohort, we have 239 patients who received chemotherapy-based myeloablative conditioning and 157 patients who received TBI-based myeloablative conditioning regimen.

Most patients in our study had B-ALL and Philadelphia-negative disease. Over half of our patients were in first complete remission prior to their haplo-HCT. Most patients also received some other form of GVHD prophylaxis, mainly cyclosporin and mycophenolate, and roughly half of the patients have bone marrow as their stem cell transplant source.

Most of the transplant in patient-related baseline characteristic were comparable between the study cohort. The main causes of death between both studies groups were disease relapse and infection.

There were more death related to graft versus host disease in TBI cohort and there were slightly more increased risk of death from graft failure or graft rejection in chemotherapy cohort. The death from veno-occlusive disease were slightly more in chemotherapy based and there were few patients who died from second re-malignancy in chemotherapy arm.

Subsequently, we did a univariate analysis of haplo-HCT outcomes between the TBI and the chemotherapy cohorts and showed that TBI-based conditioning was associated with significantly reduced non-relapse mortality, and hence resulted in better leukemia-free survival compared to chemotherapy recipient. Other transplant outcomes were fairly comparable.

Subsequently, we did a multivariate Cox regression model after adjusting for all the transplant patients-related characteristics, and showed that the TBI-based myeloablative conditioning was associated with increased risk of acute graft versus host disease grade II to IV without impacting the incidence of chronic graft versus host disease.

In this analysis, we also found that use of peripheral blood as the stem cell source also increased the risk of acute graft versus host disease, as expected.

Next, we looked at relapse incidence and non-relapse mortality. Surprisingly, TBI or chemotherapy-based, the choice of conditioning regimen did not impact the relapse incidence in multivariate model. However, TBI was still associated with better non-relapse mortality compared to chemotherapy.

Here again, patient who received bone marrow graft had better non-relapse mortality compared to recipient of peripheral blood graft.

The disease status prior to transplant, of course, was associated with the increased relapse incidence. Patients who had beyond CR1 disease status or active disease or advanced-stage disease right before the haplo-HCT were at higher risk of leukemia relapse after stem cell transplantation.

Finally, leukemia-free and overall survival -- TBI was associated with better leukemia-free survival with hazard ratios 0.71 and significant P-value compared to chemotherapy arm without impacting the overall survival. Interestingly, here again, the use of peripheral blood as stem cell source was associated with poor leukemia-free and also overall survival.

Finally, GVHD and relapse-free survival. The choice of conditioning regimen did not impact the incidence of GRFS between the study cohort, but use of peripheral blood stem cell graft was associated with poor GVHD and relapse-free survival in our study.

In conclusion, in adult patients with ALL who are undergoing myeloablative conditioning followed by haploidentical stem cell transplant with post-transplant cyclophosphamide, the TBI-based myeloablative conditioning seems to be resulting in better non-relapse mortality and better leukemia-free survival compared to chemotherapy-based myeloablative conditioning.

Hence, it should be preferred. The choice of conditioning regimen did not impact overall survival or GVHD relapse-free survival, and TBI-based conditioning was associated with an increased risk of acute graft versus host disease grade II to IV in our study.

Still here, the disease relapse remains the principal cause of mortality after stem cell transplant. This is a retrospective registry-based study. Our findings should be verified in a prospective fashion where you have a uniform conditioning regimen, disease status, and ideally stratified by measurable residual disease status.