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A Step Toward Comprehensive Transplant Solutions for Aplastic Anemia

Askar, Medhat MD, PhD1; Hanna, Rabi MD2

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doi: 10.1097/TP.0000000000003343
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Aplastic anemia is a rare, life-threatening blood disorder characterized by pancytopenia, hypocellular bone marrow, and the absence of underlying malignancy.1 Its incidence in the United States and Europe is approximately 2 per million per year but higher in Asia approaching 4–6 per million per year.2 Historically, severe aplastic anemia (SAA) was an almost uniformly fatal prognosis, especially for young children with sudden severe pancytopenia. Subsequently, the prospects of survival have improved through the development of effective therapies including immune suppressive therapy (IST) and hematopoietic cell transplantation (HCT) from matched sibling. Generally, it has been accepted that HCT from matched sibling is the first line of therapy for children and young adult patients (<40 y).3 However, fully matched unrelated donors (HLA-A, B, C, DRB1) from worldwide registries can be identified for about 80% of Caucasians and for much lower percentages of persons of other races and ethnicities.4 In real world experience, the decision to offer HCT for SAA is more nuanced because some older patients can tolerate the toxicities of potentially curative HCT. Thus, HCT or IST may be appropriate, depending on disease severity and the availability of appropriate HLA-matched donor.5 Currently, alternative HCT donor options including less matched related and unrelated donors are being considered for patients with SAA.

In their article published in this issue, Park et al6 investigate the timely and important question of which alternative donor source is more advantageous for transplantation in SAA patients. One of the remarkable findings of this study is the comparable outcomes among SAA patients who received transplants from HLA-matched (8/8) donors, HLA-mismatched (7/8) unrelated donors, and haploidentical donors using total body irradiation (TBI) based regimen in terms of 3-y overall survival (OS), failure-free survival (FFS), cumulative incidence of graft-failure, transplant-related mortality (TRM), and graft versus host disease (GVHD). The comparability of outcomes among 7/8 and 8/8 HLA-matched unrelated donors challenges our conventional wisdom based on a number of previous studies showing that 7/8 HLA mismatch unrelated donors conferred significantly increased risk GVHD, TRM, and lower OS.7 The ability to accomplish these comparable outcomes increases the probability of finding unrelated donors from 20%–70% to 70%–90% based on ethnicity.4 This also allows incorporation of non-HLA selection considerations such as younger donor age, gender match, ABO match, CMV status, killer immunoglobulin receptors, and CCR5–/– donors for HIV recipients across 30 million donors currently available in unrelated donor registries worldwide. Because of the hypothetical existence of nontransplant options in SAA, conservative donor selection is always pursued until alternative options’ safety and efficacy are demonstrated in other HCT indications wherein HCT is the standard of care. A phase II multicenter clinical trial (NCT02793544) to assess the safety of (4/8–7/8) HLA-mismatched unrelated donors using posttransplant high-dose cyclophosphamide (PTCy) based GVHD prophylaxis in patients with hematological malignancies is currently underway.

In addition, the Park et al study reported comparable outcomes among recipients of haploidentical donors and the above 2 donor categories.

The resurgence of haploidentical donor transplantation over the past decade is a major advance in the field of HCT. Several platforms have been exploited to maximize its safety and efficacy, such as ex vivo T-cell depletion techniques with positive-CD34+ selection, “mega-dose” of purified CD34+ cells, or selective depletion of T-cells, and T-cell replete approaches that include use of intensified immune suppression, TBI, or PTCy. In malignancy settings, haploidentical transplantation has become a well-accepted alternative donor source, with several studies reporting survival comparable to matched unrelated donors.8

In recent years, the indications for haplo HCT have been expanded from hematological malignancies to include nonmalignant disease such as SAA. However, there is a paucity of literature about the use of haplo HCT in the setting of SAA. Unlike the majority of Haplo approaches using PTCy, Park et al rely on high-dose TBI. A Brazilian group published in 2015 outcomes of 16 SAA patients (age 5–39 y) who underwent haplo HCT using a hybrid regimen with Fludarabine (Flu)—PTCy and rabbit antithymocyte globulin (ATG) 2.5 mg/kg per day on days 4 to 2 and TBI dose (200–600 cGy) reduced-intensity conditioning regimen with PTCy.9 Another prospective phase II study by the Hopkins group reported 100% OS in 13 patients with median age 30 y (age 11–69 y) who had haplo HCT using ATG, Flu, PTCy, and TBI (200 cGy).10 In another retrospective report from European Society for Blood and Marrow Transplantation,11 the author noted better OS in patients who received upfront ATG, Flu, PTCy, and low TBI 200 cGy who yielded a higher 2-y OS (93% [81%–100%] compared with non-PTCy based regimens 64% [41%–87%], P = 0.03) in univariate analysis. Table 1 summarizes the findings of these 3 studies.

TABLE 1. - Summary of haploidentical HCT studies in SAA
Study Patients number Age median (range) y HSC source Graft failure/loss aGVHD cGVHD Median follow-up OS
Esteves et al9 16 17 (5–39) BM (13) PBSC (3) 1 Failure2 Loss 20% 20% 355 d 1 y OS = 67.1(95% confidence interval: 36.5%-86.4%)
DeZern et al10 13 30 (11–69) All BM None 15.3% 15.3% 21 mo 1 y OS = 100%
Prata PH11 33 20.4 (2.5–45.4) BM 17/33PB 14/33 BM and PB 2 /33 7 Failure4 Loss 23% 10% 35.9 mo 2 y OS = 78%PTCy protocol OSPTCy yielded a higher 2-y OS (93%)
GVHD, graft vs host disease; OS, overall survival; PTCy, posttransplant high-dose cyclophosphamide.

This study by Park et al included a large number of patients (n = 46) who haplo HCT, which is larger than prior studies. Notably, they reported very low-graft failure that led to excellent FFS of 82.3% for haplo HCT. Also, this study had an excellent follow-up period with median follow-up of 70.8 mo in the 8/8 patients, 75.3 mo in the 7/8 patients, and 29.9 mo in the haplo patients. FFS is an important metric when reviewing HCT literature in SAA given the high incidence of graft failure historically and need for second HCT in this patient population.

This study used a high-dose TBI-based conditioning regimen, which potentially contributed to better engraftment and less secondary graft failure. The TBI dose was (600–800 cGy) with majority of patients receiving unrelated donors getting 800 cGy and 20% of patients getting haplo HCT getting 800 cGy.

It is important to recognize that higher radiation dose contributes to higher secondary malignancy risk as reported by Baker et al.12 Notably, Park et al lowered the TBI dose in the later cases from 800 to 600 cGy to lower TRM. Further studies are warranted to investigate the ideal TBI dose the lowers the TRM even further without compromising engraftment.

Currently haplo HCT with PTCy is being studied in multicenter prospective study in North America by the Bone Marrow Transplant Clinical Trials Network (CTN 1502 CHAMP study; NCT02918292). This phase II study of haplo HCT to assess OS at 1-y post–haplo HCT in SAA patients up to the age of 75 y. The study has opened in July, 2017, and aims to finish enrollment in early 2021.

Consideration of donor-specific HLA antibodies (DSAs) is critical in haplo HCT. In this study, 2 patients were included without desensitization in spite of having DSA of 5000–10 000 median fluorescence intensity. Although these 2 cases did not experience delayed engraftment, this practice is at odds with the European Society for Blood and Marrow Transplantation Consensus Guidelines recommending desensitization at this level of DSA.13

Taken together, 7/8 HLA-matched unrelated donors and haploidentical donors can be considered acceptable alternative donor choices for adult patients who failed immune suppressive therapy. The plethora of haploidentical transplant platforms show great promise, and several approaches have been reported to have survival comparable to matched unrelated donors. Although the nuances of conditioning therapy choice, donor choice, and other clinical variables that impact HCT outcomes will be determined by ongoing and future studies so that all aplastic anemia patients who need a transplant will have a suitable donor.


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