Haploidentical transplants for patients with graft failure after the first allograft
Authors: Piyanuch Kongtim, Maria Bittencourt, Samer A. Srour, Jeremy Ramdial, Gabriela Rondon, Julianne Chen, Issa Khouri, Oran Betul, Uday Popat, Amanda Olson, Qaiser Bashir, Elizabeth J. Shpall, Partow Kebriaei, Richard E. Champlin, Stefan O. Ciurea
Journal: American Journal of Hematology (2020)

Successful engraftment with donor hematopoietic cells is an essential goal of allogeneic hematopoietic stem cell transplantation (AHSCT) to ensure adequate long-term hematopoiesis and provide effective graft-vs-tumor effect. Graft failure (GF), defined as either absence of initial donor cell engraftment (primary GF, PGF) or loss of donor cells after initial engraftment (secondary GF, SGF), is an infrequent, but serious complication after AHSCT with incidence of 5%-10% in patients with hematologic malignancies.1-3 Patients with GF are at high risk of early non-relapse mortality (NRM) due to prolonged cytopenia, increase risk of life threatening infections and hemorrhage. Second AHSCT is most of the time the only salvage option which needs to be performed urgently as higher NRM and relapse may occur without a functioning graft. Haploidentical (HAPLO) donor may be the alternative donor choice for a second AHSCT due to its wide availability for almost all patients in need of an urgent transplant. Here we analyzed outcomes of consecutive 31 adult patients with a diagnosis of hematologic malignancy, who received an unmanipulated HAPLO AHSCT as a salvage treatment for either PGF (N = 18) or SGF (N = 13). This was after the first allograft between October1995 and September2017 at the University of Texas MD Anderson Cancer Center. Details on outcome definitions and statistical analyses are available in supplemental material. The main diagnosis was acute myeloid leukemia (AML; N = 13, 42%). Donor type for the first AHSCT was HAPLO (N = 19, 61.3%), umbilical cord blood (N = 8, 25.8%), matched-related (N = 2, 6.5%) and matched unrelated donor (N = 2, 6.5%). Before the first transplant, four of 22 (18.2%) tested patients had donor-specific anti-HLA antibodies (DSA) positivity (>2000 mean fluorescence intensity) and all of these four patients had PGF despite receiving desensitization treatment with plasma exchange, rituximab, IVIg +/− donor buffy coat infusion,3 while T cell rejection was noted in 15 patients. For the rescue transplant, patients received hematopoietic stem cells from a HAPLO donor, 7/19 (36.8%) from the same HAPLO donor. Fifteen patients (48.4%) received non-myeloablative conditioning with fludarabine, cyclophosphamide and 2 Gy of total body irradiation (Flu-Cy-TBI) with post-transplant cyclophosphamide, mycophenolate mofetil and tacrolimus. The median time from the first to second stem cell infusion was 48 days (range 27-147 days), or 20 days from GF diagnosis. (supplemental material 2). None of the patients had DSAs at the time of second transplant against the HAPLO donor. Of 31 patients, 27 patients had neutrophil engraftment with a median time of 16 days (range 8-27 days), and the corresponding cumulative incidence at 28 days of 87.5% (Figure 1A). Three patients died before day+28 without neutrophil engraftment and one patient died of PGF at 43 days post-transplant. Among seven patients who received stem cells from the same HAPLO donor, only four patients (57%) engrafted successfully but eventually died of NRM within 100 days, and three patients (42.8%) died of NRM before engraftment. The cumulative incidence of platelet engraftment at 60 days was 48.4% (Figure 1A) and the median time was 20 days (range 13-87 days). Among 27 engrafted patients, 25 and two patients had full donor and mixed chimerism, respectively. Cumulative incidence of acute graft-versus-host disease (GVHD) grade 2-4 and 3-4 at 100 days was 35.5% and 13.8%, respectively. Chronic GVHD incidence was only 14.9% at 3 years. Cumulative incidence of NRM at 1 year was 59% and of relapse was 14.9% at 3 years (Figure 1B). The median overall survival (OS) was 5.2 months (95% CI 2.5-11 months), and 3-year OS was 22% (95% CI 10.9%-44.1%). Median progression-free survival (PFS) was 4.5 months (95% CI 1.7-11 months), or 20.9% at 3 years (95% CI 7.4-39.1 years). In multivariable analysis, factors independently associated with better OS were a diagnosis of AML/MDS (hazard ratio; HR 0.23, 95% CI 0.09%-0.58%, P = .002) and use of Flu-Cy-TBI conditioning (HR 0.27, 95% CI 0.09-0.75, P = .012), while transplantation using the same HAPLO donor was associated with poor OS with HR of 2.90 (95% CI 1.07-7.92, P = .037). All of these factors had similar impact on PFS with HR of 0.27 (95% CI 0.11-0.69, P = .006) for AML/MDS, 0.29 (95% CI 0.11-0.77, P = .013) for Flu-Cy-TBI regimen, and 2.32 (95% CI 1.09-6.22, P = .043) for the same HAPLO donor transplant. Patients with AML/MDS had 3-year OS of 28% (95% CI 14.5%-63.8%) compared with only 9% (95% CI 3%-39%) for those with other hematologic malignancies (P = .004) (Figure 1C). Regarding type of conditioning, 3-year OS of patients receiving Flu-Cy-TBI regimen was 42.9% (95% CI 16%-76.6%) and 6.7% (95% CI 2%-23.5%) for those receiving other regimens (P = .043) (Figure 1D). The OS was 0% in patients who were transplanted with the same HAPLO donor (Figure 1E). Best OS was seen in patients with AML/MDS, who received Flu-Cy-TBI conditioning and different HAPLO donor (64.3% OS at 3 years, 95% CI 25.7%-94.8%) (Figure 1F). The negative impact of disease other than AML/MS, and transplantation with the same donor for HAPLO transplants on survival was mainly related to increase in NRM. The AML/MDS patients had significantly lower NRM than other disease types (subdistribution HR, SHR 0.21, 95% CI 0.07-0.62, P = .005). In contrast, same HAPLO donor transplant independently predicted higher NRM (SHR 5.43, 95% CI 1.65-8.41, P = .011). Other factor that significantly predicted higher NRM was hematopoietic cell transplant comorbidity index (HCT-CI) with 16% (95% CI 6%-29%) NRM risk increment for each one additional HCT-CI score (P = .002). Due to the fact that only four relapses occurred, univariable analysis and MVA for relapse were not performed. Nevertheless, none of patients with low disease risk index or those receiving Flu-Cy-TBI regimen relapsed during the follow-up period. Primary causes of death were infection (N = 9), graft failure (N = 4), relapse (N = 3), GVHD (N = 4) and organ failure (N = 3). Second AHSCT is usually the only salvage option for patients with GF, with 10%-30% OS for patients with hematological malignancies. Up to 40% of patients may still experience GF after the second AHSCT.4-6 In the present study, we analyzed outcomes of HAPLO AHSCT to rescue patients with GF. We hypothesized that a second transplant using HAPLO donors can be performed quickly and effectively salvage for most patients with engraftment failure. Our analysis showed that a rescue HAPLO AHSCT using non-ablative conditioning with Flu-Cy-TBI regimen provided better survival, compared with all other approaches we employed to date. It is likely that this regimen provides enough immunosuppressive effects to ensure engraftment with excellent tolerability and low toxicity. As mentioned above, best survival was noted in patients with AML/MDS, who received Flu-Cy-TBI conditioning and a different HAPLO donor (with different mismatched haplotype) for those who had a prior HAPLO AHSCT. Notably, all patients who had a second transplant with the same donor had a high engraftment failure rate and all died of NRM. Similar with results from the previous studies,4-6 the main reason for poor survival in our patient cohort was early NRM, where more than half of the patients died of NRM within 1 year after transplant. This is particularly true in patients with high comorbidities, suggesting that appropriate transplant procedure modification can help decrease mortality, and increase post-transplant survival for patients with GF. A different HAPLO donor with different mismatched haplotype might be a preferred donor choice to avoid a second rejection especially for those with suspected T cell rejection as cause of GF. In conclusion, urgent haploidentical transplantation using non-ablative conditioning is associated with better outcomes compares with our previous experience and compares favorably to reported data. Selecting a donor with a different mismatched haplotype for the second haploidentical transplant was associated with higher engraftment rate, lower NRM and better survival. No relevant conflict of interest to declare. P.K. contributed with statistical design, data analysis, interpretation of results and manuscript writing, M.B., S.A.S., J.R. contributed with manuscript writing, I.K.O.B., U.P., A.O., Q.B., E.J.S., P.K, R.E.C contributed with treatment of the patients, S.O.C contributed with statistical design, data analysis and interpretation of the results and manuscript writing. All authors reviewed and approved the manuscript. Appendix S1. Supplemental Material. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.