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. Author manuscript; available in PMC: 2022 Jun 24.
Published in final edited form as: Semin Hematol. 2018 Sep 20;56(3):183–189. doi: 10.1053/j.seminhematol.2018.09.002

Post-transplantation cyclophosphamide to facilitate HLA-haploidentical hematopoietic cell transplantation: mechanisms and results

Hany Elmariah 1, Ephraim J Fuchs 1
PMCID: PMC9229262  NIHMSID: NIHMS1507607  PMID: 31202428

Abstract

Allogeneic blood or marrow transplantation (BMT) is a curative therapy for a number of high-riskhematologic malignancies. Historically, only patients with a human leukocyte antigen (HLA)-matchedsibling or unrelated donor were able to receive this therapy, thus excluding many potential transplantrecipients. In recent years, partially mismatched related donor, or HLA-haploidentical (haplo) BMT hasexpanded the donor pool to nearly every patient in need of a transplant, particularly when using post transplantation cyclophosphamide (PTCy) to promote immune tolerance and prevent graft-versus-hostdisease (GVHD). With now over 15 years of clinical experience using this platform, long terms outcomesare well understood. We review the clinical literature and highlight the advantages and disadvantages ofhaplo BMT with PTCy.

Introduction

Since the advent of allogeneic blood or marrow transplantation (BMT), the selection of a donor has focused on minimizing alloreactivity between the immune systems of the donor and recipient, thus minimizing graft-versus-host disease (GVHD) and graft rejection. The intensity of alloreactivity is proportional to the degree of mismatch between donor and recipient for genes of the human leukocyte antigen, or HLA, locus.1–3 The historical paradigm for selecting a donor, thus, placed HLA matching as highest priority. To decrease non-HLA genetic disparity, the standard preferred BMT donor is a matched sibling donor (MSD), though only 30% of patients have an available MSD.4 Thus, registries of volunteer adult donors have been established to locate appropriate HLA-matched unrelated donors (MUDs), though the likelihood of finding a donor can vary from 10–80% depending on ethnicity.4,5 Identification of an unrelated donor can delay BMT by weeks to months, which has been correlated with negative outcomes including relapse and non-relapse mortality (NRM).6

Despite the preference for genetically similar donor/recipient pairs, there may be benefits to genetic disparity. We now understand that a graft-versus-tumor (GVT) effect provides a major therapeutic benefit of an allogenic BMT.7 The key to the GVT effect is the recognition of cancer cells as being foreign to the graft, thus eliciting an allogenic immune response.8,9 Two types of antigens on leukemia cells can elicit a GVT response: ubiquitously expressed recipient antigens (expressed on normal recipient cells and cancer cells) and tumor-specific antigens (expressed only on leukemia cells).8,10,11 Normal recipient antigens recognized by donor immunity include both HLA antigens and minor histocompatibility antigens12. Hence, while the presence of abnormal leukemia antigens is static, the alloreactivity against normal recipient antigens can be intensified by selecting donors who are genetically disparate from the recipient. This can be accomplished directly, by selecting HLA mismatched donors, or indirectly by selecting unrelated donors who are inherently more likely than related donors to recognize minor histocompatibility antigens as foreign.7,13

The challenge of finding a fully HLA matched donor and the benefits of using HLA-disparate donors have motivated efforts to optimize immune tolerance enough to use HLA haploidentical (haplo) donors for BMT. 14 By definition, a haplo donor shares by common inheritance exactly one HLA-haplotype with the recipient and is mismatched for a variable number of HLA genes on the unshared haplotype. Each parent or biological child of a patient is guaranteed to be HLA-haploidentical (haplo). A sibling has a 50% chance of being a haplo match, in addition to a 25% chance of being a full HLA match. Thus, almost all patients have at least one haplo donor, and most have several. This high frequency of readily available donors allows for rapid donor selection with elimination of a costly and prolonged unrelated donor search. Early efforts with this approach were marred by the immense alloreactivity created by HLA mismatch, resulting in high rates of graft failure, GVHD, and mortality.1,3,15 Hence, the primary challenge of haplo BMT has been to control this alloreactivity to eliminate toxicity, but also maintain a balance with immune reconstitution and GVT.

The number of HLA loci tested for a “match” varies by institution and circumstance, in part due to an understanding that mismatching can have variable effects based on the underlying disease, donor source, and specific type of mismatch.16 Generally, with increased mismatch comes higher rates of GVHD, lower rates of relapse, and in many circumstances, worse survival.16,17 When considering degree of mismatch, prior data shows that matching at HLA A, B, C, and DRB1 (8/8 match) contributes most to long term survival, while HLA DQB1 and DPB1 have little to no impact on survival.17 Mismatch is also characterized by directionality, where the graft-versus-host direction is defined by presence of HLA antigens in the recipient that are not present in the donor, and host-versus-graft direction is defined by HLA antigens present on the donor but not on the recipient.18 Though these directional mismatches would suggest increased risk of GVHD and graft rejection, respectively, clinical evidence has demonstrated mixed results.19–22

Early Data

Cyclophosphamide is a potent immune inhibitor which can lead to immune tolerance and decrease GVHD and graft rejection.23,24 Morris Berenbaum showed that cyclophosphamide was more effective at delaying the rejection of major histocompatibility complex (MHC)-mismatched mouse skin allografts when the drug was given after rather than before the graft.24 More than 20 years later, a method of inducing durable transplantation tolerance was developed by Mayumi, Himeno, Nomoto and colleagues in Fukuoka, Japan.23 Tolerance of MHC-matched skin allografts was achieved by infusing mice with ≥50 million allogeneic spleen cells followed in 48–72 hours by the intraperitoneal injection of high dose cyclophosphamide. While this simple method was successful at inducing donor hematopoietic chimerism and skin allograft tolerance in MHC-matched donor/recipient pairs, tolerance of MHCmismatched cells required conditioning of the recipient with anti-lymphocyte serum prior to the cell infusion.23,25 The Johns Hopkins BMT group applied post-transplantation cyclophosphamide (PTCy) as GVHD prophylaxis in the post-BMT setting in early mouse models.26 In those studies, mice received nonmyeloablative (NMA) conditioning with fludarabine and total body irradiation (TBI), and then posttransplant cyclophosphamide (PTCy) 200 mg/kg intraperitoneally on day +3. Administration of PTCy resulted in low rates of GVHD despite the presence of MHC mismatching. Additionally, durable engraftment was achieved, and was noted to be enhanced with higher doses of TBI (200 cGy) and higher donor cell doses (107 cells/kg).

This regimen was translated to hematologic malignancies patients receiving HLA-haploidentical bone marrow in a two cohort study intended to determine if cyclophosphamide could improve engraftment.27 In cohort 1, three patients were conditioned with fludarabine 30 mg/m2 on days −6 to −2, TBI 200 cGy on day −1, and PTCy 50 mg/kg on day +3. Patients then continued on oral immunosuppression with mycophenolate mofetil on days +4 to +35, and tacrolimus from days +4 to day ≥ +50. In cohort 2, 10 additional patients received the same regimen, plus the addition of cyclophosphamide 14.5 mg/kg on days −6 and −5. In this cohort, 80% of patients achieved full donor chimerism. In the entire study, three patients experienced grade 2 GVHD and three patients experienced grade 3 GVHD. While this trial confirmed that HLA mismatched related BMT can result in engraftment, long term graft failure and severe GVHD approached 60%.

In 2008, results of a landmark, two-center study established PTCy as an acceptable platform for GVHD prophylaxis after haplo BMT.28 Twenty-eight patients received flu/cy/TBI conditioning with PTCy on day +3. An additional 40 patients received this regimen with an additional dose of PTCy 50 mg/kg on day +4 (Figure 1). Graft failure occurred in 13% of the patients treated. The incidence of acute GVHD was 34% and of severe acute GVHD was 6%. Incidence of extensive chronic GVHD was 5% in the group who received 2 doses of PTCy, compared to 25% in the group who received only 1 dose (p=0.05). NRM and relapse at 1 year were 15% and 50%. Overall survival (OS) at 2 years was 36%. These results established what has become the standard haplo BMT with PTCy treatment regimen.

Fig. 1.

Fig. 1.

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Schema showing the original “Hopkins Regimen” for haploidentical transplant using fludarabine,cyclophosphamide, and total body irradiation conditioning, bone marrow graft, and post-transplant cyclophosphamide.

Post-Transplant Cyclophosphamide Mechanism

Though PTCy can mitigate alloreactivity and reduce the incidences of graft rejection and GVHD, the mechanism for this effect is not well understood. Animal models have shown that PTCy eliminates both alloreactive donor T-cells that are necessary for GVHD and donor-reactive intrathymic host T-cells that cause graft rejection.29,30 Meanwhile, PTCy has been reported to spare foxp3+ regulatory T cells (Tregs) due to their high expression of aldehyde dehydrogenase, an enzyme that metabolizes cyclophosphamide.14,31 This allows for the immune tolerance needed for HLA mismatched BMT. Other studies have emphasized the role of clonal deletion in the induction of tolerance by cyclophosphamide, with suppressor cells emerging late after a breakdown in intrathymic clonal deletion.32,33 Future studies are warranted to better characterize the mechanism of tolerance induced by PTCy and, thus, elucidate interventions to help optimize this BMT strategy.

Clinical Outcomes with the Original Haplo PTCy Regimen

Early protocols confirmed the relative safety of the regimen developed at Johns Hopkins (the “Hopkins” regimen). In 2010, a retrospective study of 185 patients demonstrated NRM of 15%, acute GVHD of 31%, and chronic GVHD of 15%, and no differences were observed with increasing degree of HLA mismatch.34 A subsequent report of 210 patients (including the original 185) treated with the same regimen supported earlier results with incidences of GVHD of 27%, chronic GVHD of 13%, and NRM of 18% with five year follow-up.35 Longer follow-up also confirmed that there is no significant risk of post-transplant lymphoproliferative disorder when using this regimen.36

There are currently no published prospective randomized trials comparing haplo BMT using the Hopkins regimen to other donor sources, such as volunteer unrelated donors or umbilical cord blood. One study presented the results of two parallel phase 2 trials, each with 50 leukemia or lymphoma patients undergoing either NMA haplo BMT with PTCy or double unrelated donor umbilical cord blood transplantation (UCBT). NRM, relapse, and overall survival at one year after transplantation were 7%, 45% and 62% after haplo BMT and 24%, 31%, and 54% after UCBT.37 These outcomes provided clinical equipoise for a multi-center, prospective randomized phase III trial of these two approaches for patients with leukemia or lymphoma (NCT01597778); accrual has recently completed.

Multiple retrospective studies have compared NMA haplo BMT with PTCy to other donor platforms. Di Stasi, et al. compared outcomes of 227 patients with myeloid malignancies undergoing BMT with either MSD, MUD, or haplo donors using the PTCy regimen.38 There was no severe acute GVHD in the haplo group, which was significantly superior to the 11% incidence of severe acute GVHD in recipients of grafts from MSDs. Survival outcomes and NRM were comparable in the three groups. In a retrospective study by the Center for International Blood and Marrow Transplant Research (CIBMTR), 987 lymphoma patients received either NMA haplo BMT with PTCy (n=180) or MSD (n=807) transplants.39 Risk of chronic GVHD was lower in the haplo group (12% versus 45%). Acute GVHD was similar in the two groups (27% versus 25%). OS in the haplo group was 61%, versus 62% in the MSD group (p=0.82). Another study compared outcomes of 917 lymphoma patients following either haplo BMT with PTCy or either of two MUD platforms.40 In the haplo group, rates of chronic GVHD were significantly lower than MUD (13% versus >30%). Outcomes were otherwise similar, with the haplo transplants yielding 60% 1year OS, 36% relapse, and 8% severe acute GVHD.

Rather than comparing donor types, McCurdy, et al. compared outcomes of NMA haplo BMT with PTCy to expected outcomes using the refined disease risk index (DRI).41,42 In this retrospective analysis of 372 patients, safety outcomes were favorable with NRM of 8%, severe acute GVHD of 4%, and chronic GVHD of 13%. Reported efficacy outcomes included 3-year relapse, PFS, and OS of 46%, 40%, and 50%, respectively. When stratified by DRI scores, the authors found that outcomes of haplo BMT with PTCy were comparable to those predicted by the DRI for matched donors, suggesting that this BMT platform is comparable to matched donor BMT. The same group later compared haplo versus MSD versus MUD BMT in 684 patients, all of whom received PTCy.43 Based on composite endpoints of GVHD-disease free survival and chronic GVHD-disease free survival, they found no differences in outcomes by donor type.

Overall, these studies (summarized in Table 1) confirmed that haplo BMT with PTCy results in outcomes that are comparable to matched donor sources in terms of survival, though with potentially less chronic GVHD. Relapse remains the primary driver of mortality in patients treated with this transplant platform.

Table 1.

Summary of results of select studies of Haplo BMT with PTC

MODIFICATION TO
ORIGINAL
REGIMEN		 STUDY HAPLOS(N) Diseas
es		 F/
U		 CONDITIO NING GVHD
Prophylax
is		 GRAF
T
TYPE		 ENGR
AFT		 NR
M		 R
R		 SEV
ERE
ACU
TE
GVH
D		 CHRO
NIC
GVHD		 EF
S		 OS
Luznik.
BBMT.
2008.28 		68 Mixed 2
y		 Flu/Cy/TBI PTCy/CNI/
MMF		 BM 87% 15
%		 58
%		 6% 7% 26
%		 36%
NONE Kasamon.
BBMT.
2010.34 		185 Mixed 1
y		 Flu/Cy/TBI PTCy/CNI/
MMF		 BM 84% 15
%		 N/
A		 N/
A		 15% 35
%		 N/A
Munchel.
Ped Rep.
2011.35 		210 Mixed 5
y		 Flu/Cy/TBI PTCy/CNI/
MMF		 BM 87% 18
%		 55
%		 5% 13% 27
%		 35%
Brunstein.
Blood.
2011.37 		50 Mixed 1
y		 Flu/Cy/TBI PTCy/CNI/
MMF		 BM 98% 7
%		 45
%		 0% 13% 48
%		 62%
McCurdy.
Blood.
2015.41 		372 Mixed 3
y		 Flu/Cy/TBI PTCy/CNI/
MMF		 BM 90% 11
%		 46
%		 4% 13% 40
%		 50%
Ghosh.
JCO.
2016.39 		180 Lymph
oma		 3
y		 Flu/Cy/TBI PTCy/CNI/
MMF		 BM,
PB		 95% 15
%		 37
%		 8% 12% 48
%		 61%
GRAFT Kanate.
Blood.
2016.40 		185 Lymph
oma		 3
y		 Flu/Cy/TBI PTCy/CNI/
MMF		 BM,
PB		 94% 17
%		 36
%		 8% 15% 47
%		 60%
Bashey.
JCO.
2017.45 		191 Mixed 2
y		 Mixed PTCy/CNI/
MMF		 PB 93% 16
%		 28
%		 N/A 41% 54
%		 57%
O’Donnell.
BMT.
2016.46 		43 Mixed 3
y		 Flu/Cy/TBI PTCy/CNI/
MMF		 PB 93% 12
%		 24
%		 5% 19% 65
%		 66%
CONDITIO
NING 		Di Stasi.
BBMT.
2014.38 		32 AML/M
DS		 3
y		 Flu/Mel/
Thiotepa		 PTCy/CNI/
MMF		 BM,
PB		 97% 24
%		 33
%		 0% 11% 30
%		 N/A
Ciurea.
Blood.
2015.47 		104 AML 3
y		 MA
(Mixed)		 PTCy/CNI/
MMF		 BM,
PB		 90% 14
%		 44
%		 7% 30% N/
A		 45%
Cieri.
BBMT.
2015.51 		40 Mixed 1
y		 Treosulfan
/Flu/Mel		 PTCy/Sirol
imus/MM
F		 PB 100% 17
%		 41
%		 8% 20% 48
%		 56%
Solomon.
BBMT.
2012.48 		20 Mixed 1
y		 Flu/Bu/Cy PTCy/CNI/
MMF		 PB 100% 10
%		 40
%		 10% 35% 69
%		 50%
Raiola.
BBMT.
2013.50 		50 Mixed 1
y		 MA
(Mixed)		 PTCy/CNI/
MMF		 BM 90% 18
%		 26
%		 6% 26% 51
%		 62%
Kasamon.
BBMT.
2018.52 		55 Mixed 2
y		 Flu/Cy/TBI PTCy/CNI(
60
days)/MM
F		 BM 89% 4
%		 47
%		 7% 11% 49
%		 71%
GVHD PPX Bolanos-
Meade.
Blood.
2012.53 		14 Sickle
Cell
Aplasti
c		 1
y		 ATG/Flu/Cy/TBI PTCy/Sirol
imus/MM
F		 BM 57% 0
%		 N/
A		 0% 0% N/
A		 100
%
PATIENT DeZern.
BBMT.
Blood.
2017.70 		13 Anemia
Mixed
(Elderly
)		 2
y		 ATG/Flu/C
y/TBI		 PTCy/CNI/
MMF		 BM 100% 0
%		 0
%		 0% 13% 0
%		 100
%
POPULATION BBMT.2017.70 13 Anemia
Mixed
(Elderly)		 2
y		 ATG/Flu/Cy/TBI PTCy/CNI/
MMF		 BM 100% 0
%		 0
%		 0% 13% 0
%		 100
%
Kasamon.JCO.2015.66 271 3
y		 Flu/Cy/TBI PTCy/CNI/
MMF		 BM
2nd
Degree		 90% % % 3% 100% % 46%
DONOR
TYPE 		Elmariah.BBMT.2018.57 33 Mixed 1
y		 Flu/Cy/TBI PTCy/CNI/
MMF		 BM 94% 5
%		 31
%		 3% 10% 64% 95
%
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Abbreviations: Haplo=haploidentical, F/U=follow-up, y=years, PTCy=post-transplant cyclophosphamide,flu=fludarabine, mel=melphalan, bu=busulfan, TBI=total body irradiation, ATG=antithymocyte globulin, MA=myeloablative, CNI=calcineurin inhibitor, MMF=mycophenolate mofetil, BM=bone marrow, PB=peripheral blood stem cells

Modifications to the Haplo BMT with PTCy Regimen (Table 1)

Graft Source

While the initial haplo transplant with PTCy regimen employed marrow grafts, many centers prefer peripheral blood stem cell transplantation (PBSCT). In a prior large prospective study, PBSCT has proven to cause higher risk of chronic GVHD but lower engraftment failure in a population of mostly matched donor transplants who did not receive PTCy.44 Given the impact of PTCy at lowering chronic GVHD rates, other investigators have evaluated PBSCT with PTCy versus bone marrow transplant with PTCy. Bashey et al. compared 671 patients and found marrow resulted in significantly lower acute GVHD (25% versus 42%) and chronic GVHD (20% versus 41%), but higher relapse rates (45% versus 28%) compared with PBSCT. Engraftment, NRM, and OS were similar in the two groups. In subgroup analysis, they confirmed that the difference in relapse rates was found in patients with myeloid diseases but not lymphoma.45 In a similar study of 86 patients, no differences were found in GVHD rates, but relapse was higher in the marrow group (58% versus 24%).46 Though prospective data are needed, relapse rates may be improved with PBSCT, while PTCy may mitigate the risk of GVHD.

Conditioning

Noting that relapse is the primary cause of treatment failure following NMA haplo BMT with PTCy, many studies have examined the effects of intensifying the conditioning regimen. The CIBMTR published results of a retrospective study comparing any myeloablative regimen with haplo BMT and PTCy versus myeloablative MUD BMT.47 Haplo BMT with PTCy was associated with significantly lower acute GVHD (16% versus 33%) and chronic GVHD (30% versus 53%). However, MUD BMT was associated with superior engraftment at 30 days (90% versus 97%). No differences were detected in 3-year relapse or survival.

Solomon et al. conducted a prospective clinical trial using flu/busulfan (bu)/cy myeloablative conditioning with haplo PBSCT and PTCy.48 In this selected group of 20 patients, cumulative incidence of acute GVHD was 30%, severe acute GVHD was 10%, chronic GVHD was 35%, NRM was 10%, OS was 69%, and DFS was 50%. The same group later compared MSD, MUD, and haplo with PTCy transplants in 271 patients, with patients receiving either myeloablative flu/bu/cy, or the traditional NMA flu/cy/TBI regimen.49 Rates of extensive chronic GVHD were lower in the haplo group (38% versus 54% versus 54%). No other significant differences were found. Probabilities of two-year OS were 76%, 67%, and 64% and of DFS were 53%, 52%, and 60% for MSD, MUD, and haplo respectively.

Groups in Italy have also pursued myeloablative haplo bone marrow transplantation with PTCy. The first compared outcomes across donor types using thiotepa/bu/flu with a modified PTCy given on days +3 and +5 in patients as old as 66 years.50 As with NMA regimens, severe acute GVHD and chronic GVHD rates were low at 12% and 10%, respectively. However, NRM was higher at 18%, and relapse rates were favorable at 26%, despite many patients having active disease at the time of transplant. With a median follow-up of only 8 months, OS was 51%. A more recent prospective study used a treosulfan/melphalan myeloablative regimen prior to haplo PBSCT with PTCy.51 Noting the use of peripheral blood and sirolimus instead of calcineurin inhibitor, the rate of severe acute GVHD was 7.5% and chronic GVHD was 20%. Overall relapse rate was 35%, NRM was 17%, and OS was 54% at one year.

Immunosuppression

Though the original haplo PTCy regimen included tacrolimus from days 5–180 and mycophenolate from days 5–35 post-transplantation, some studies have attempted to change the GVHD prophylaxis regimen. Recently, our group reported results of a prospective trial using the original flu/cy/TBI and marrow grafts and comparing tacrolimus through post-transplantation day 120, 90, or 60.52 Stopping at day 60 still resulted in severe GVHD rates <10% and chronic GVHD rates <15%., which has been practice changing at our institution. We have also selectively substituted sirolimus instead of tacrolimus after haplo PBSCT given similar outcomes in published studies, and a unique toxicity profile with decreased renal and neurologic toxicity.53–57 A number of trials are ongoing to evaluate both the duration and type of GVHD prophylaxis following haplo PTCy transplants.

Toxcities

Despite the favorable NRM and GVHD rates associated with haplo BMT with PTCy, certain toxicities are more frequently associated with this regimen. In a retrospective study of mostly myeloablative transplants comparing MSD, MUD, UCBT, mismatched unrelated donor (MMUD), and haplo BMT with PTCy, rates of cytomegalovirus infection (CMV) were highest in the haplo group at 74%, though relapse and OS rates were not higher.58 Thus, it is recommended that CMV levels be checked weekly for at least 2 months and patients remain on antiviral prophylaxis for 1 year following BMT with PTCy.

Though not studied specifically in the context of PTCy, hemorrhagic cystitis is a known complication following cyclophosphamide-containing myeloablative conditioning.59 More recent data have suggested that cyclophosphamide containing NMA conditioning does not increase the risk of hemorrhagic cystitis, though there was an association with haplo donors, especially in the presence of BK virus.60 Anecdotally, hemorrhagic cystitis is frequently observed following haplo BMT with PTCy. Mesna has proven effective as a bladder protectant that can reduce rates of hemorrhagic cystitis and, thus, is included in the PTCy regimen and is recommended by consensus guidelines.61,62 When hemorrhagic cystitis occurs weeks or months after transplant, viral infections such as BK virus and adenovirus should be considered as likely etiologies.63,64 Typically, hemorrhagic cystitis after BMT with PTCy is self-limited, resolving within a few weeks without intervention.

As with all BMT regimens, fevers are a frequent complication of haplo BMT with PTCy. While these may be due to infection, fevers in the first few days after transplantation (and before PTCy) are often due to cytokine release associated with the therapy. In a retrospective analysis of 762 patients, patients receiving myeloablative haplo BMT had the highest incidence of fevers (84%), followed by NMA haplo (46%), myeloablative MUD (23%) and myeloablative MSD (12%) transplants.65 In the haplo groups, fevers were specifically associated with HLA class II mismatches at HLA-DRB1 and –DPB1. Mismatches at HLA-DRB1 were also associated with higher risk of grade II-IV GVHD.

Unique Applications of Haplo BMT with PTCy

Older Patients

The low NRM associated with haplo BMT with PTCy makes this regimen acceptable in older patients. In a retrospective study of 271 patients ranging from 50–75 years of age, one year NRM was 8% for the entire cohort.66 When stratified further, NRM was 8% for patients of ages 50–59, 8% for patients of ages 60–69, and 7% for patients between the ages of 70 to 75. Three-year OS by age was 48%, 45%, and 44% for patients in their 50s, 60s, and 70s, respectively. While BMT can be tolerated in patients above 70, sibling donors are often suboptimal due to advanced age and associated comorbidities. In most cases, the patient’s offspring provides a younger, healthier donor option. A recently presented abstract reported significantly lower NRM when using donors <30 years old (6%), compared with 30–45 years old (16%), and >40 years old (15%), independent of the patient’s age.67 There was a trend towards improved survival in the younger donor group, though this did not reach statistical significance (p=0.08).

Non-Malignant Conditions

In adults with severe sickle cell disease (SCD), BMT offers a potential cure but only ~20% of patients will have a MSD.68 Bolanos-Meade, et al. applied the BMT with PTCy regimen in this patient population and were able to find an unaffected haplo or matched donor for 100% of referred patients.53 Despite the addition of antithymocyte globulin (ATG) to improve engraftment, graft failure occurred in 43%. Still, 10 of the 17 patients transplanted were asymptomatic at long-term follow-up. With no need for a GVT effect, immunosuppression was continued for a full year and 1 patient experienced GVHD affecting only the skin. By increasing the TBI dose to 400cGy in a subsequent trial, the rate of graft failure was reduced to 6%.69

In aplastic anemia, haplo BMT with PTCy has also proven successful. DeZern et al. used a similar regimen with ATG and standard haplo BMT with PTCy followed by 1 year of immunosuppression in 16 patients with refractory severe aplastic anemia.70 On long-term follow-up, engraftment was 100% and all patients were transfusion independent. Mild GVHD was observed in 2 patients, both of whom completely recovered. NRM was 0%. A multicenter trial is ongoing to validate these results (NCT02918292).

Partially Mismatched Donors Other Than First-Degree Relatives

Though over 90% of patients requiring transplant have a first-degree haplo or matched donor, there are circumstances when first-degree relatives cannot donate, such as for women with cytotoxic antibodies against disparate HLA molecules in their children. Two studies have evaluated the safety of PTCy using donors who are not first-degree relatives.71 The first used partially HLA-mismatched unrelated donors (mMUDs; ≥5/10 HLA antigen match) with NMA conditioning and PTCy in 20 patients. In the second trial, 33 patients received NMA BMT with PTCy from haplo related donors who were second- or third-degree relatives, such as nieces, nephews, cousins, or even grandchildren.57 Incidence of acute GVHD was ~25%, chronic GVHD was 10–16%, and NRM was ~6%. OS at 1-year was 75–95%. Given these outcomes, haplo donors who are not first-degree relatives should be considered as an alternative donor source.

Our Approach

At Johns Hopkins University, PTCy has become standard for all of our allogeneic BMTs. When using this approach, there appear to be no significant differences in outcomes associated with haplo versus matched donors. The equivalence of haplo transplants with PTCy and matched sibling or matched unrelated donor transplants, as seen in retrospective analyses,39,40,47 has had two major effects on donor selection. First, when transplantation is urgent because of a perceived high risk of relapse or clinical deterioration, we believe it is permissible to forego a lengthy unrelated donor search and instead opt to use a haplo donor. Second, there may be situations in which a haplo donor may be preferred over an older, HLA-matched sibling. Donor age is especially important in light of the improved outcomes of unrelated donor transplants with younger donors72 and the increased incidence of clonal hematopoiesis in older donors.73 Though marrow grafts are perfectly acceptable for patients with acute leukemia in complete remission with no evidence of minimal residual disease or with lymphoma in chemo-sensitive relapse, filgrastim-stimulated peripheral blood is being used increasingly for patients at high risk of relapse or graft failure.

Conclusions

Haplo BMT with PTCy has emerged as one of the most popular alternative donor platforms used by the BMT community. With over 15 years of experience, it is now clear that this platform is safe, with low rates of GVHD and NRM. Its efficacy appears to be similar to matched donor sources, with comparable long-term OS in a number of published studies, though this possibility needs to be tested in prospective, randomized clinical trials.

Haplo BMT with PTCy offers a number of logistical advantages over other donor sources. Haplo donors are more readily available, expanding the donor pool to nearly 100% of patients needing a transplant. Moreover, these donors are relatives who are emotionally invested and reliable, thus allowing for rapid mobilization times of 2–4 weeks in most cases. For older patients, haplo offspring or even grandchildren may allow for healthier marrow with avoidance of donor-derived clonal hematopoiesis. In the case of relapse, haplo donors are easily able to donate donor lymphocyte infusions. Finally, the cost of related donor BMT may be lower than unrelated donor or UCB transplants.74

The primary limitation of haplo BMT with PTCy is delayed immune reconstitution which can lead to higher rates of some infections such as CMV. Additionally, there is a theoretical potential for increasing the risk of donor derived leukemias with the use of an alkylating agent after stem cell infusion. However, the primary cause of long term mortality is disease relapse. Hence, future studies should focus on novel strategies to decrease relapse without additional toxicity, such as maintenance drug or cell therapies, further shortening immunosuppression, or choosing donors with a higher potential for alloreactivity.

Acknowledgments

Supported by P01 CA15396 from the U.S. National Cancer Institute

Footnotes

Conflicts of Interest/Disclosures

The authors declare that they have no conflicts of interest or competing financial or personal relationships that could inappropriately influence the content of this article.

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References

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