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HLA-mismatched bone marrow transplantation in severe aplastic anemia

Bone Marrow Transplantation volume 52, pages 1347–1348 (2017)Cite this article

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Hematopoietic stem cell transplantation (SCT) can be curative for patients with severe aplastic anemia (SAA).1, 2 Concerns about graft failure and graft-versus-host disease (GVHD), more so for human leukocyte antigen (HLA) -mismatched donors, have impeded the utility of SCT for these patients. The introduction of post-SCT cyclophosphamide (PTCy) has been shown to decrease alloreactivity in the host-versus-graft and graft-versus-host directions and could be particularly well suited for SAA patients.3 Only a few patients in two recent reports have documented outcomes of patients with SAA treated with a haploidentical transplant and PTCy-based GVHD prophylaxis, both using non-myeloablative (NMA) conditioning with fludarabine, cyclophosphamide and 2 Gy total body irradiation (TBI).4, 5 Concern for higher rejection rate, both primary and secondary, has prompted us to use a more intense conditioning regimen, as previously described.6 Here, we report clinical outcomes in transfusion dependent (n=6, 5 were refractory to first line immunosuppressive therapy, one patient received hypomethylating agent for hypoplastic MDS subsequently diagnosed as AA) SAA patients who underwent HLA-mismatched bone marrow SCT from haploidentical (n=2) and 9/10 matched unrelated donors (n=4) at our center between January 2010 and May 2013. Conditioning regimen consisted of melphalan (140 mg/m2) on day-8, thiotepa (5 mg/kg) on day-7 and fludarabine (160 mg/m2) on days −6 to −3. GVHD prophylaxis consisted of cyclophosphamide (50 mg/kg) on days +3 and +4, tacrolimus for 180 days and mycophenolate mofetil for 100 days post transplant. Median age of patients at the time of SCT was 37 years (range 21–50), median Karnofsky performance score was 90 (range 80–100) and median time from diagnosis to transplant was 9 months (range 2–15 months). Of the six patients, two of them had a concomitant PNH clone>20% prior to SCT. All patients engrafted the donor cells with 100% chimerism noted for both myeloid and T-cell lineage at day +30 post SCT. Of the four-long-term survivors, 100% donor (lymphoid and myeloid) chimerism was noted starting from day 30 until 1 year post SCT in three patients and for up to 6 months for one patient (follow-up care was transferred to an outside institution and was found to be disease-free at 1 year post SCT). Median time to neutrophil and platelet engraftment was 16 and 13 days, respectively (Table 1). Acute GVHD was seen in three patients (grades-1, 2 and 4 each) and led to death in one patient who had a 9/10 MUD SCT (Table 1). No chronic GVHD (cGVHD) or disease relapse was noted. After a median follow-up of 949 days (range 735–1617), 4/6 (66.6%) patients (two haploidentical and two 9/10 MUD) were alive, fully engrafted without cGVHD.

Table 1 Characteristics and outcomes of patients with SAA treated with PTCy-based GVHD prophylaxis and a mismatched graft
Full size table

Only about 25–30% of SAA patients have an HLA-identical related donor, and the probability of finding a fully HLA-matched unrelated donor for patients with hematologic disorders needing SCT varies substantially based on their ethnicity.7 Hence, when a fully HLA-matched unrelated donor is not identified, HLA-mismatched transplantation provides an option with curative potential otherwise not available to many patients. More recently, introduction of PTCy prophylaxis has shown encouraging results in patients with hematologic malignancies receiving SCT from haploidentical and 9/10 MUD donors.8, 9 Concerns remain, however, with the low intensity NMA conditioning regimen especially for patients with non-malignant diseases regarding a higher rate of primary or secondary graft rejection, and the need to retransplant a subgroup of these patients.4 Here, we report our experience with a more intense, melphalan-based conditioning regimen for SAA patients, in which all patients achieved prompt engraftment with no mixed chimerism post SCT, alleviating the concern for secondary graft failure. Acute GVHD incidence appears well controlled with PTCy-based GVHD prophylaxis and no cGVHD was observed. Our results show that application of a more intense conditioning is feasible and could be used for counseling patients who express concerns of secondary graft failure with NMA options. Our experience also adds to the growing body of evidence that supports the use of PTCy for HLA-mismatched SCT recipients and increase the donor pool for SAA patients.

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Financial disclosure: The authors have no relevant financial disclosures to report.

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  1. Department of Stem cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    L S Bachegowda, M V Shah, L W Veltri, U Popat, P Anderlini, J Chen, G Rondon, R E Champlin & S O Ciurea

  2. Institutul Clinic Fundeni, Bucharest, Romania

    A Tanase

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  1. L S Bachegowda
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Bachegowda, L., Shah, M., Veltri, L. et al. HLA-mismatched bone marrow transplantation in severe aplastic anemia. Bone Marrow Transplant 52, 1347–1348 (2017). https://doi.org/10.1038/bmt.2017.146

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