Introduction
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most effective options for hematological malignancies. Many patients can survive for a long period after HSCT. A healthy human leukocyte antigen (HLA)-identical sibling donor (ISD) is preferred, but is usually unavailable for many HSCT patients. HLA-unrelated matched donor HSCT and unrelated cord blood HSCT are also options, but the donor pools of the Unrelated Donor Program and cord blood banks are still relatively small; thus, it takes a long time to find a suitable donor, and some patients might relapse while waiting for the HSCT. Over the past 2 decades, HLA-partially matched related donors (PMRDs) have arisen as a viable option. Several protocols have been established worldwide, and substantial progress including enhanced graft-versus-host disease (GVHD) prophylaxis, new conditioning regimens, novel strategies for relapse prophylaxis, and improved supportive care strategies have been developed in the field of PMRD HSCT, and increasing numbers of patients have benefited from these techniques. Thus, here, we review the literature on PMRD HSCT.
Studies of PMRD HSCT with ex vivo T-cell depletion
Perugia protocol (Italy)
Since the 1990s, at the University of Perugia, Aversa
et al. [
1-
3] have employed extensive
ex vivo T-cell depletion (TCD) (1×10
4-3×10
4 CD3
+ cells/kg) and megadose stem cell transplantation (CD34
+ selection, 9×10
6-13.8×10
6 CD34
+ cells/kg), which has successfully overcome the HLA disparity. Peripheral blood progenitor cells are mobilized by recombinant human granulocyte colony-stimulating factor (G-CSF) and depleted of T cells using CD34
+ cell immunoselection. In this protocol, primary engraftment is achieved in most patients (≥93%), and the median times for myelogenous and platelet engraftment are 10.2 days (range: 9-17 days) and 17.2 days (range: 10-29 days), respectively [
1-
3]. The infusion of large numbers of highly purified CD34
+ cells is associated with a low incidence of GVHD (acute GVHD, 0%-8%; chronic GVHD, 7.1%), despite a lack of post-transplantation immunosuppression. In 1998, Aversa
et al. [
2] reported that among 43 patients with high-risk acute leukemia, 11 of 23 patients with acute lymphoblastic leukemia (ALL) as well as 2 of 20 patients with acute myeloid leukemia (AML) experienced a relapse. Transplantation-related mortality (TRM) was 40%. After a median follow-up of 18 months (range: 8-30 months), 12 of the 43 patients were alive and disease-free. In the recent phase II study involving a large-scale series of PMRD HSCT conducted for adults with acute leukemia at a high risk of relapse (AML, 67; ALL, 37), relapse occurred in 9 of 66 patients receiving transplantation in remission and 17 of 38 receiving transplantation in relapse; additionally, 38 patients died due to non-leukemic causes [
3]. However, this approach was complicated by the high toxicity of the conditioning regimen and high TRM; the harvest of larger numbers of CD34
+ cells may impose considerable demand on donors and cell pheresis services. The presence of fewer CD34
+ cells (<10×10
6/kg) increases the rate of rejection, delays engraftment and immune reconstitution, and increases the risk of infectious complications [
4]. In addition, the probability of event-free survival (EFS) for patients transplanted in relapse is poor (4%) (Table 1) [
3].
Tuebingen protocol (Germany)
At University of Tuebingen in Germany, Bethge
et al. [
6,
7] investigated a new regimen using graft CD3/CD19 depletion with anti-CD3 and anti-CD19 coated microbeads. For CD3/CD19 depletion, which was performed by “negative selection,” T- and B-cell depletion was profound (4.4-log decrease). In addition to
ex vivo CD3 depletion, the anti-CD3 mAb OKT 3 was applied in the conditioning regimen in order to deplete remaining host T cells. In this protocol, the grafts contain not only CD34
+ stem cells, but also significantly more graft-facilitating cells such as natural killer (NK) cells, monocytes, and granulocytes (Table 2). This leads to improved engraftment and immune reconstitution. Federmann
et al. [
8] reported that engraftment is sustained and quick in the Tuebingen protocol even without megadoses of CD34
+ stem cells. NK cell engraftment was quick due to the large number of NK cells contained in the graft, reaching normal values on day+ 20. Although T- and B-cell reconstitution is delayed in this case, it is faster than that reported after CD34
+ selection [
8].
Bethge
et al. [
6,
7] reported that all patients were engrafted with full donor chimerism by days 14-26 after HSCT with a median time of 12-13 days (range: 10-21 days) to>500 granulocytes/μl, 11 days (range: 7-38 days) to>20 000 platelets/μl, and more than 2-4 weeks to full donor chimerism in all patients. Although the incidence of grade II–IV GVHD was high (48%), most cases were not severe (grades II, III, and IV in 10, 2, and 2 cases, respectively), and only 1 patient who received the highest T cell dose developed lethal grade IV GVHD. Only 3 patients suffered from limited chronic GVHD. However, 20 of 29 (69.0%) patients died: 12 due to relapse, 7 due to infections, and 1 due to GVHD. Overall survival (OS) was 31% with a median follow-up of 241 days; EFS and OS were only 35% at 12 months. Therefore, these transplants are still associated with a substantial risk of relapse and TRM (Table 1).
Studies on PMRD HSCT without ex vivo TCD
Although TCD has successfully overcome the HLA disparity, it is still associated with prolonged immune deficiencies, increased risks of infectious complications, and high TRM. Consequently, several conditioning regimen protocols for PMRD HSCT without ex vivo TCD have been reported by researchers from China (Peking University), America, and Korea.
GIAC protocol (Peking University, China)
At Peking University, a protocol called “GIAC,” which involves the
in vivo modulation of T cell functions in the recipient and donor as well as adjustment of the dose of donor HSCs, was used for PMRD HSCT. This protocol includes 4 elements: “G,” donor treatment with G-CSF to induce immunological tolerance; “I,” intensified immunological suppression to both promote engraftment and prevent GVHD; “A,” the inclusion of antithymocyte globulin (ATG) to prevent GVHD and graft rejection; and “C,” a combination of G-CSF-primed bone marrow (G-BM) harvests and G-CSF-mobilized peripheral blood stem cell (G-PB) harvests as the source of stem cell grafts [
9].
Engraftment
Wang
et al. [
10] reported the largest cohort of PMRD HSCT thus far treated uniformly using the GIAC protocol without
in vitro TCD modality. Among 756 patients with leukemia, the median times for myelogenous and platelet engraftment were 13 days (range: 8-49 days) and 16 days (range:5-195 days), respectively. Advanced disease stage and fewer CD34
+ cells in allografts were associated with high risks of myelogenous and platelet engraftment failure; in addition, a small number of mononuclear cells in allografts were associated with a high risk of platelet engraftment failure [
10]. However, there was no significant association between the extent of HLA disparity and time for myeloid or platelet recovery [
10,
11]. These results suggest a greater number of CD34
+ cells in allografts are preferable to ensure rapid platelet engraftment, especially in patients with advanced-stage disease, which is also associated with delayed platelet recovery [
11].
Mesenchymal stem cell (MSC) infusion is safe and possibly accelerates hematopoietic recovery in adult patients undergoing ISD HSCT [
12]. We recently conducted an open-label randomized phase II clinical study to assess the outcome of MSC co-infusion (3×10
5-5×10
5 cells/kg) during PMRD HSCT. Within 100 days, the time to a platelet concentration of>50×10
9 cells/L was significantly faster in the treatment group than the control group (22 vs. 28 days, respectively;
P = 0.036). No immediate or long-term toxic side effects related to MSC infusion were observed, and the cumulative occurrence of GVHD, relapse, leukemia-free survival (LFS), and OS were comparable between the treatment and control groups [
13].
GVHD
At Peking University, all patients receive cyclosporine A (CsA), mycophenolate mofetil (MMF), and short-term methotrexate (MTX) for GVHD prophylaxis. In our previous studies, the 100-day cumulative incidences for grades II–IV and III–IV acute GVHD were 40%-55% [
9,
10,
14-
16] and 13.4%-23.1%, respectively [
10,
14,
16]. The 2-year cumulative incidences for total and extensive chronic GVHD were 52.9%-73.6% [
9,
10,
14,
15] and 23.4%-46.9%, respectively [
10,
14]. We also demonstrated that the cumulative incidences of acute and chronic GVHD are comparable between PMRD and ISD cohorts [
9]. There are several possible reasons for the lower incidence of GVHD after PMRD HSCT. First, grafts using an
in vitro mixture of G-PB and G-BM stem cells maintain T cell hyporesponsiveness. Second, the addition of ATG to the conditioning regimen can potently delete T cells
in vivo in the long-term, preventing GVHD with no increase in the incidence of relapse [
9,
17-
19]. Finally, the application of G-CSF on day 5 post-HSCT may further regulate T cell function [
14,
19].
We found that some elements in allografts are associated with GVHD, including higher CD4/CD8 cell ratio (≥1.16), lower CD56
dim/CD56
bright NK cell ratio (≤8.0), and higher dose of CD4
+ CD45RA
+CD62L
+ cells (>0.22 × 10
8/kg) [
20-
22]. We recently investigated the effects of interleukin (IL)-17-producing T cells (i.e., Th17 and Tc17 cells) on acute GVHD and found that patients who received a higher dose of Th17 cells in G-BM (>8.5×10
4/kg) or Tc17 cells in G-PB (>16.8× 0
4/kg) exhibited a significantly higher incidence of acute GVHD (
P = 0.005 and 0.001, respectively); the percentages of both Th17 and Tc17 cells decreased significantly after
in vivo G-CSF application. Therefore, the application of G-CSF
in vivo may aid the reduction of the occurrence of acute GVHD via decreased IL-17 secretion by T cells [
23]. Huo
et al. [
24] recently reported that HLA-B mismatch is an independent risk factor for acute GVHD. In addition, killer immunoglobulin-like receptors (KIRs) recognize human leukocyte antigen C and B epitopes on target cells, thereby regulating NK cell activity. Therefore, the presence of any individual donor-activating KIR gene may influence GVHD. We found that the KIR ligand-ligand mismatch model is a good predictor of acute GVHD (hazard ratio (HR): 3.812,
P = 0.002). We also observed that the presence of donor-activating KIR2DS3 contributes to both acute and chronic GVHD [
25].
Relapse and management
At Peking University, Huang
et al. [
16] reported that among the 250 PMRD HSCT recipients, 45 (AML, 13; ALL, 32) experienced relapse after transplantation; of these, 22 (AML, 6; ALL, 16) were from the high-risk group. The 3-year probabilities of relapse of patients with AML and ALL in the standard-risk group were 11.9% and 24.3%, respectively, while those in the high-risk group were 20.2% and 48.5%, respectively. We also demonstrated that the incidence of relapse did not differ significantly between ISD and PMRD HSCT cohorts [
9]. Several factors including advance disease status, higher CD4/CD8 ratio in G-BM (≥1.16), lower CD56
dim/CD56
bright NK cell ratio (≤8.0), and delayed lymphocyte recovery on day 30 after HSCT were associated with an increased probability of relapse in our protocol [
20,
21,
26,
27].
Although PMRD HSCT has stronger graft-versus-leukemia (GVL) effects in leukemia patients, relapse remains an important problem. Donor lymphocyte infusion (DLI), which has been successfully used to treat leukemia relapse, can be followed by a high rate of severe GVHD, pancytopenia, or severe infections. To overcome these shortcomings, we designed a modified DLI strategy including G-CSF-mobilized peripheral blood cells followed by short-term immune suppression after DLI (CsA, blood concentration of 150-250 ng/ml for 2-4 weeks or a low dose of MTX (10 mg) once per week for 2-4 weeks). Huang
et al. [
28] reported that 20 patients experienced relapse after HSCT received modified therapeutic DLI, and 8 of them survived in complete remission for a median of 1118 days. The 2-year probability of LFS was 40%. We also evaluated the role of modified DLI in the prophylaxis of relapse. Huang
et al. [
29] reported that of 33 patients with advanced leukemia who received modified prophylactic DLI, 16 achieved disease-free survival (DFS) with a median follow-up of 18 months. No GVHD-related death or transfusion-related pancytopenia was observed. OS at 1 and 1.5 years was 69.0% and 50.2%, respectively. In a recent study including 88 patients with advanced-stage acute leukemia, the 2-year cumulative incidence of relapse was lower in patients who received prophylactic DLI than those who did not (36% vs. 55%, respectively;
P = 0.017). The 3-year probabilities of OS and LFS were higher in patients who received prophylactic DLI than those who did not (OS: 31% vs. 11%,
P = 0.001; LFS: 22% vs. 11%,
P = 0.003). Multivariate analysis for relapse showed that the use of prophylactic DLI after HSCT was an independent prognostic factor [
30]. These results suggest that modified DLI may increase the survival of patients with advanced-stage acute leukemia who receive PMRD HSCT.
Monitoring of minimal residual disease (MRD) is also important. Interventions prior to the occurrence of hematological or pathological relapse based on post-HSCT MRD could improve the outcomes of high-risk patients. Several studies demonstrate that leukemia-specific fusion genes such as
PML-RARA,
BCR-ABL,
AML1-ETO, and
CBFB-MYH11 detected by real-time quantitative PCR (qPCR) can be used to detect and monitor MRD [
31]. In patients without a leukemia-specific fusion gene, Wilms’ tumor gene-1 (
WT1), which is overexpressed in approximately 90% acute leukemia cases, is a useful marker for monitoring MRD [
32].
WT1 expression>1.05% was indicative of a higher probability of relapse (HR= 4.774,
P<0.001) and
WT1 expression≥0.60% was significantly associated with lower DFS [
33]. In addition, multiparameter flow cytometry (FCM) is a useful method for monitoring MRD [
34]. Patients who were FCM
+ after transplantation had a higher cumulative incidence of relapse than those who were FCM
- (54% vs. 8%;
P<0.001). Moreover, an FCM
+ status after the second month post-HSCT was a predictor of leukemia relapse [
35].
On the basis of the observations mentioned above, we performed a prospective study investigating the impact of risk stratification-directed interventions on transplantation outcomes in patients with standard-risk acute leukemia receiving allo-HSCT according to MRD status. Subjects in modified DLI groups had a significantly lower cumulative risk of relapse and significantly longer DFS. In multivariate analyses, MRD
- status after transplantation (OR= 0.511,
P<0.001) and receiving modified DLI (OR= 0.436,
P<0.006) were significantly associated with longer DFS. These data suggest risk stratification-directed interventions with modified DLI improve transplantation outcomes [
36].
TRM and survival
At Peking University, Huang
et al. [
14] reported that 39 of 171 patients died due to transplant-related complications. The causes of transplantation-related death included GVHD, infection, and other causes (e.g., heart and hepatic failure) in 13, 21, and 5 cases, respectively. The 100-day, 1-year, and 2-year TRM rates in the standard-risk group were 9.1%, 17.4%, and 19.5%, respectively, while those in the high-risk group were 12.7%, 29.4%, and 31.1%, respectively. In a recent report, 64 (AML, 22; ALL, 42) of 250 patients died due to transplant-related complications; the TRM rates on day 100 after transplantation in the standard- and high-risk groups were 6.8% and 5.9% for AML and 6.9% and 25.9% for ALL, respectively. At 3 years, the TRM rates in the standard- and high-risk groups were 19.4% and 29.4% for AML and 21.2% and 50.8% for ALL, respectively [
16].
In a study involving 250 patients with acute leukemia, the probabilities of 3-year LFS were 70.7% and 55.9% for AML and 59.7% and 24.8% for ALL in the standard- and high-risk groups, respectively [
16]. For chronic myeloid leukemia (CML) patients, the probabilities of 1- and 4-year LFS were similar in patients in the chronic phase (CP) 1, CP2/complete remission (CR) 2, accelerated phase, and blast crisis [
37]. For myelodysplastic syndromes (MDS) patients, the 2-year probability of LFS was 65% [
38]. Our recent study concerning the GVL effect associated with PMRD compared to ISD grafts for high-risk acute leukemia revealed that the 2-year cumulative incidence of relapse was significantly lower in PMRD (26%) than ISD recipients (49%) (
P = 0.008). Additionally, the 2-year cumulative incidence of non-relapse mortality (NRM) was comparable between recipients of PMRD (34%) and ISD grafts (38%) (
P = 0.85), and the 3-year probability of OS was higher in PMRD (42%) than ISD recipients (20%) (
P = 0.048). Our comparisons suggest that PMRD transplants can achieve a stronger GVL effect than ISD for high-risk acute leukemia patients [
39]. Several factors are associated with the superior LFS after PMRD HSCT, including early disease status, lower CD4/CD8 ratio in G-BM, higher CD56
dim/CD56
bright NK cell ratio, higher day 30 absolute lymphocyte count (ALC-30) post-HSCT, the number of KIR ligands carried by patients, and short interval from diagnosis to HSCT (within 7 months and 450 days of diagnosis for MDS and CML patients, respectively) [
20,
21,
25-
27,
37,
38].
Immune reconstitution
Different immune cell subsets recover at different rates after PMRD HSCT. The effects of early lymphocyte recovery on transplant outcomes in patients with hematological malignancies after PMRD HSCT were investigated. Multivariate analysis revealed that ALC-30 exceeding the cutoff value of 300 cells/μl was associated with improved OS and LFS, reduced relapse, and decreased TRM in both adult and pediatric patients. Therefore, the recovery of ALC-30 might influence transplant outcomes following PMRD HSCT [
26,
27]. However, Chang
et al. [
40] reported that T cell subset and dendritic cell subgroup cell counts in the first 90 days after grafting are lower in PMRD than ISD HSCT recipients. The difference was most striking for CD4
+ and CD4
+ naïve T cells: the counts of reconstituted CD4
+ cells were significantly lower in PMRD patients on days 30, 60, 90, and 120 than in ISD patients and did not reach normal levels until day 360 in both ISD and PMRD patients. T cell lymphopenia renders patients susceptible to infections. However, in our transplant protocol, compensatory expansion of monocytes and cytotoxic T lymphocytes (CTL)—especially cytomegalovirus (CMV)-pp65 peptide-specific CTLs (CTL
CMV) with the central memory CD45RO
+ CD62L
+ cell phenotype—accompanies the recovery of CD8
+ T cells; this population of cells may proliferate and differentiate into effector memory T cells stimulated by CMV antigen and may contribute toward reducing the incidence of CMV disease [
41]. Considering the early immune constitution following PMRD HSCT, novel approaches aiming to improve the recovery of immune reconstitution are urgently required. On the basis of the potent T cell growth factor activity of IL-2 [
42], a randomized clinical trial evaluating the effect of IL-2 on immune reconstitution after PMRD HSCT is currently being performed at Peking University.
Concerning the reconstitution of NK cells, Chang
et al. [
43] observed that the absolute number of CD56
bright NK subset among white blood cells and number of CD56
bright NK subset recovered to the donor’s level by day 14, increased continuously and peaked by day 60 in those who never developed GVHD and by day 120 in all 43 patients. The ratio of CD56
dim/CD56
bright NK subsets in patients eventually reached a level similar to that of healthy controls by day 120 in those who never developed GVHD and by day 180 in all 43 patients.
Health-related quality of life (HRQoL)
With the development of the PMRD HSCT technique, increasing numbers of patients with hematological disease have achieved long-term survival. HRQoL should be considered an important index for evaluating the efficacy of PMRD HSCT. Therefore, we evaluated the HRQoL of 177 PMRD HSCT recipients using the Mos 36-Item Short-Form Health Survey (SF-36) and compared the results to those of ISD HSCT recipients. PMRD HSCT recipients had higher scores in physical functioning, general health, bodily pain, vitality, and emotional role functioning than ISD recipients. In addition, PMRD HSCT recipients functioned significantly better on the physical and mental component summaries. Multivariate analysis revealed that extensive chronic GVHD strongly and negatively impacted HRQoL. In addition, male gender, lower age at HSCT, and returning to work or school were associated with positive impacts on at least one subscale. However, HLA disparity was not a risk factor for HRQoL. These results show that the HRQoL of patients receiving PMRD and ISD HSCT is comparable [
44]. Although this result is encouraging, it should be further corroborated by prospective, multicenter, and large-scale studies.
Graft selection: mixture of G-BM and G-PB or G-PB alone?
Initial studies demonstrated that G-CSF could lead to T cell hyporesponsiveness and modulate the balance between Th1 and Th2 immune responses [
45] and that G-CSF use plays an important role in immune tolerance in PMRD HSCT. At Peking University, we used a combination of G-BM and G-PB as the source of stem cell grafts [
14]. Our studies suggest that
in vivo G-CSF administration can alter the composition of BM grafts (i.e., increase the number of monocytes and dendritic cells, and downregulate CD28/CD80/CD86 expression on monocytes, B cells, and T cells) and induce T cell hyporesponsiveness in bone marrow grafts [
46]. G-CSF can also significantly decrease the expressions of 4 adhesion molecules (VLA-4, ICAM-1, L-selectin, and LFA-1) on naïve CD4
+ and CD8
+ T cells in bone marrow grafts, increase the percentages of IL-4-positive cells in naïve CD4
+ and CD8
+ T cell subsets, and lead to the polarization of bone marrow naïve CD4
+ and CD8
+ T cells from a Th1 to Th2 phenotype [
47]. We also demonstrated that T cell hyporesponsiveness and polarization of T cells from Th1 to Th2 can be maintained after mixing G-PB and G-BM in different proportions
in vitro [
48]. In addition, we investigated the impact of recombinant human IL-11 (rhIL-11) and G-CSF on bone marrow transplantation. Treating donor mice with rhIL-11 and G-CSF promotes transplant-tolerance and recipient survival [
49].
We also investigated the efficacy and feasibility of G-PB harvested for the treatment of high-risk acute leukemia patients. Compared to G-BM/G-PB transplants, G-PB resulted in inferior cumulative myeloid engraftment 30 days after transplantation (89.9% vs. 100%;
P = 0.04) but comparable 50-day cumulative platelet engraftment probability (79.6% vs. 86.0%;
P = 0.41) and cumulative incidence of grade II–IV acute GVHD (37.1% vs. 63.2%;
P = 0.058). Although both transplant protocols had similar 2-year relapse probabilities (29.6% vs. 34.0%;
P = 0.954), OS (26.8% vs. 43.2%;
P = 0.052), and DFS (26.8% vs. 42.4%;
P = 0.071), G-PB resulted in a higher incidence of 2-year non-leukemic mortality (62.5% vs. 35.1%;
P = 0.014) [
50]; this result suggests that G-PB is inferior to G-BM/G-PB transplants. Yu
et al. [
51] from the Chinese People’s Liberation Army General Hospital also investigated the efficacy and safety of PMRD HSCT with G-PB as allografts. In their study, for 21 patients with high-risk hematological malignancies, the cumulative incidence of acute GVHD on day 100 was 52.7%, and the 2-year cumulative incidence of chronic GVHD was 39.5%; the 2-year probabilities of TRM, OS, and DFS with a median follow-up of 16 months were 20.5%, 62.1%, and 55.6%, respectively. The results of this trial suggest that G-PB alone is a promising protocol in PMRD HSCT settings. Despite these findings, whether a mixture of G-BM and G-PB or G-PB alone should be chosen as an allograft in PMRD HSCT remains unclear. Therefore, more randomized clinical studies should be conducted to clarify this issue.
GIAC protocol in pediatric patients
PMRD HSCT with
ex vivo TCD including CD34
+ selection [
52,
53] or CD3/CD19 depletion [
54] is an effective option for pediatric patients with hematological malignancies. However, there are few studies in the literature about PMRD HSCT without
ex vivo TCD in pediatric patients. At Peking University, we evaluated the efficacy and safety of the GIAC protocol in 42 children below the age of 14 years, with hematological malignancies. All patients achieved stable engraftment. The median times of myeloid and platelet recovery were 14 days (range: 9-22 days) and 22 days (range: 8-90 days) after transplantation, respectively. The cumulative incidences of acute grades II–IV and III–IV GVHD were 57.2% and 13.8%, respectively. The cumulative incidences of total and extensive chronic GVHD were 56.7% and 29.5%, respectively. Twenty-seven patients survived, and the 3-year probability of LFS of all patients was 57.3% [
55]. Thus, the results suggest that PMRD HSCT without TCD is a promising option for children with indications for transplantation.
American protocol
At Duke University, Rizzieri
et al. [
56] reported a nonmyeloablative preconditioning regimen for PMRD HSCT comprising alemtuzumab 20 mg/d on days -4 to 0, fludarabine 30 mg/(m
2·d) on days -5 to -2, cyclophosphamide 500 mg/(m
2⋅d) on days -5 to -2, and GVHD prophylaxis including mycophenolate with or without cyclosporine. Ninety-four percent of patients had successful engraftment, while 8% had severe GVHD and 75% attained complete remission. The TRM and 1-year survival rates were 10.2% and 31%, respectively. However, a standard-risk group of 19 patients with aplasia or in remission at transplantation had a 1-year survival rate of 63% and a median OS time of 2.9 years. At the University of Minnesota, Brunstein
et al. [
57] reported another nonmyeloablative preconditioning regimen comprising fludarabine 40 mg/(m
2⋅d) intravenous drip (IV) from days -6 to -2, cyclophosphamide 50 mg/kg IV on day -6, and 2 Gy total body irradiation in a single dose on day -1. The cumulative incidence of myelogenous engraftment on day+56 was 96% with a median time to recovery of 16 days. The cumulative incidence of platelet engraftment on day+100 was 82% with a median time to recovery of 38 days. The cumulative incidence of grade II–IV acute GVHD on day+100 was 32%; there were no reported cases of grade III–IV acute GVHD. The cumulative incidence of chronic GVHD at 1 year was 13%. The 1-year probabilities of OS, progression-free survival, NRM, and relapse were 62%, 48%, 7%, and 45%, respectively. Munchel
et al. [
58] recently reported another protocol for nonmyeloablative PMRD HSCT, which includes high-dose post-transplantation cyclophosphamide for GVHD prophylaxis. Conditioning comprises cyclophosphamide 14.5 mg/(kg⋅d) on days -6 and -5, fludarabine 30 mg/(m
2⋅d) for 5 consecutive days starting on day -6, and 2 Gy total body irradiation given in a single fraction on day -1. There is no manipulation to deplete graft T cells. GVHD prophylaxis consists of cyclophosphamide 50 mg/kg IV each on days 3 and 4, mycophenolate mofetil 15 mg/kg orally 3 times per day (maximum, 3 g/d) from day 5 to day 35, and tacrolimus from day 5 to day 180. Among 210 recipients of PMRD HSCT, 87% experienced sustained donor cell engraftment. The cumulative incidences of grade II–IV acute GVHD and chronic GVHD were 27% and 13%, respectively. The 5-year cumulative incidence of NRM was 18%, relapse was 55%, and actuarial OS and EFS were 35% and 27%, respectively.
Korean protocol
At Pusan National University, Lee
et al. [
59] reported a protocol consisting of busulfan 3.2 mg/(kg⋅d) intravenously on days -7 and -6, fludarabine 30 mg/(m
2⋅d) intravenously on days -7 to -2, and rabbit ATG 3 mg/(kg⋅d) on days -4 to -1, which is similar to the GIAC protocol. Among the recipients, 91.6% achieved initial myelogenous engraftment at a median of 13.5 days after HSCT with a cumulative incidence of 92%. Additionally, 86.7% achieved platelet engraftment at a median of 17 days after HSCT with a cumulative incidence of 87%. The cumulative incidences of grades II–IV and III–IV acute GVHD on day+100 were 20% and 7%, respectively. The cumulative incidence of chronic GVHD was 34% at a median of 3.3 months after HSCT, and the incidences of moderate-to-severe and severe chronic GVHD were 24% and 18%, respectively. After a median follow-up duration of 26.6 months, the EFS and OS rates for patients with acute leukemia in remission, refractory acute leukemia, and MDS were 56% and 45%, 9% and 9%, and 53% and 53%, respectively. All these studies demonstrated that PMRD HSCT without
ex vivo TCD is a safe and effective option for patients with hematological malignancies (Table 3) [
5].
In summary, the studies discussed above demonstrate that the establishment and improvement of PMRD HSCT systems with or without ex vivo TCD marks the end of difficulties in finding a donor source for patients with hematological malignancies. Additional information is required to choose the best PMRD donor. A better understanding of the mechanisms of immune tolerance and immune reconstitution as well as the establishment of a more safe and effective modified DLI strategy may further decrease TRM and the relapse/progression of the disease and improve survival and HRQoL.
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