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Haploidentical Bone Marrow Transplantation Without T-Cell Depletion
Haploidentical Bone Marrow Transplantation Without T-Cell Depletion Ying-Jun Chang and Xiao-Jun Huang Approaches for haploidentical bone marrow transplantation (BMT) without T-cell depletion have been designed using new transplant strategies, including anti-thymocyte globulin (ATG) preparative regimens, granulocyte colony-stimulating factor–primed grafts, post-transplantation rapamycin, or high-dose cyclophosphamide (Cy) in combination with other immunosuppressive agents for graft-versus-host disease (GVHD) prophylaxis. These strategies ensured fast hematologic engraftment across the human leukocyte antigen (HLA) barrier with an acceptable incidence of GVHD. Long-term follow-up results from different transplant centers suggest that unmanipulated transplantation may provide an alternative strategy in the haploidentical setting without requiring the technical expertise and cost of ex vivo T-cell depletion. This review discusses immune reconstitution and factors associated with clinical outcomes following unmanipulated haploidentical hematopoietic stem cell transplantation (HSCT), and compares outcomes between unmanipulated haploidentical transplant versus HLA-matched sibling donor (MSD) transplantation, HLA-matched unrelated donor (MUD) transplantation, or unrelated double umbilical cord blood (dUCB) transplantation. Advantages and disadvantages of unmanipulated haploidentical HSCT and strategies to improve outome after haploidentical BMT without ex vivo T-cell depletion are discussed. Semin Oncol 39:653-663 © 2012 Elsevier Inc. All rights reserved.
H
aploidentical/mismatched bone marrow transplantation (BMT) offers the benefits of rapid and near universal donor availability and has been accepted worldwide as an alternative treatment for patients with hematologic malignancies who do not have a human leukocyte antigen (HLA) completely matched sibling or who require urgent transplantation.1–26 Several transplant centers reported success with transplantation of T-cell–depleted (TCD) peripheral blood stem cells (PBSC) with a low rate of graftversus-host disease (GVHD), but these transplants are associated with a high rate of rejection, slow immune reconstitution, and a substantial risk of treatment-related mortality (TRM).1,8,27–29 Therefore, many centers actively pursue BMT without T-cell depletion using unmanipulated haploidentical transplant protocols.5–7,9,30,31 The approaches used include anti-thymocyte globulin (ATG) preparative regimens for partial in vivo T-cell depletion, granulocyte colony-stimulating factor–primed grafts to Peking University People’s Hospital, Peking University Institute of Hematology, Beijing, China. The authors report no potential conflicts of interest. Address correspondence to Xiao-Jun Huang, MD, Peking University People’s Hospital, No. 11 Xizhimen South St, Beijing 100044, China. E-mail: [email protected] 0270-9295/ - see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2012.09.003
polarize the T-cell response to a TH-2 type pattern, posttransplantation rapamycin to favor development of regulatory T-cell populations, or high-dose post-transplant cyclophosphamide (Cy) to preferentially deplete alloreactive T cells. Preliminary results of haploidentical hematopoietic stem cell transplantation (HSCT) employing myeloablative or nonmyeloablative conditioning regimens followed by infusion of unmanipulated stem cell grafts have been published.12–14,32 Over the past several years, results of unmanipulated haploidentical HSCT have substantially improved due to enhanced GVHD prophylaxis, the development of new conditioning regimens, novel strategies for relapse prophylaxis, and improved supportive care. The objective of this review is to provide up-to-date data on long-term follow-up results, immune reconstitution, factors associated with clinical outcomes, and strategies to improve outcomes after unmanipulated haploidentical HSCT.
CURRENT STATUS OF UNMANIPULATED HAPLOIDENTICAL TRANSPLANTATION Recently, long-term follow-up results were reported by researchers from transplant centers in the United States, Japan, China, and elsewhere. At Johns Hopkins University, 210 patients with hematologic malignancies who received nonmyeloablative, HLA-haploidentical transplantation with high-dose, post-transplantation Cy
Seminars in Oncology, Vol 39, No 6, December 2012, pp 653-663
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654
were retrospectively analyzed (Table 1). Munchel et al31 found that the cumulative incidences of grades II–IV acute GVHD and chronic GVHD were 27% and 13%, respectively. The cumulative incidences of relapse and non-relapse mortality were 55% and 18%, respectively. Three-year overall survival (OS) and eventfree survival (EFS) were 41% and 32%, respectively. At Hyogo College of Medicine (Japan), Kaida et al33 summarized 351 cases of haploidentical stem cell transplantation. Among them, 100 patients underwent a myeloablative preconditioning regimen (haplo-full) and 251 patients received a reduced-intensity conditioning (RIC) regimen (haplo-mini). Acute GVHD (grades II–IV) was observed in 36 % for haplo-full and 20% for haplomini, respectively. OS at 5 years was 30% for haplo-full and 40% for haplo-mini. Multivariate analysis showed that disease status (complete remission [CR]) was the significantly favorable variable (P ⫽ .0026). At Pusan National University (Korea), Lee et al9 assessed 83 patients enrolled in haploidentical transplant trials using RIC with busulfan, fludarabine, and ATG. The cumulative incidences of neutrophil engraftment, grades II–IV acute GVHD, chronic GVHD, and TRM after HSCT were 92%, 20%, 34%, and 18%, respectively. After a median follow-up time of 26.6 months (range, 16.8 – 78.8 months), EFS and OS rates were 56% and 45%, respectively, for patients with acute leukemia (AL) in remission; 9% and 9%, respectively, for patients with refractory AL; and 53% and 53%, respectively, for patients with myelodysplastic syndrome. At Peking University, from May 2002 to December 2010, 820 patients with hematologic malignancies, including 206 in the high-risk group, received transplantation from haploidentical family donors without T-cell depletion. Eight hundred eleven patients (99%) achieved sustained, full donor chimerism. The incidence of grades II–IV acute GVHD was 42.9%, and that of grades III–IV was 14.0%, which was not associated with the extent of HLA disparity. EFS rates for low- and high-risk patients were nearly 45% and 70%, respectively.34 Taken together, long-term follow-up results from different transplant centers suggest unmanipulated transplant may provide an alternative strategy in the haploidentical setting without requiring the technical expertise and cost of ex vivo T-cell depletion as compared with TCD haploidentical transplant. More recently, Muramatsu et al35 reported 53 pediatric patients with aplastic anemia (AA) who underwent unmanipulated haploidentical transplantation. They found that the probability of grades III–IV acute GVHD in patients transplanted from a one locus-mismatched related donor (1MMRD) was significantly higher than that in patients transplanted from an HLAmatched related donor (MRD) (P ⬍.001). The probability of 5-year OS of patients transplanted from 1MMRD was comparable to that of patients transplanted from a MRD, but it was significantly better than
Y.-J. Chang and X.-J. Huang
that of patients transplanted from two to three locimismatched related donors and HLA-matched unrelated donor (MUD). These data reveal that an HLAmismatched related donor, especially 1MMRD, could be an acceptable donor candidate for children with AA requiring urgent transplantation. Sano et al36 have extended non–TCD HLA haploidentical stem cell transplantation to treat refractory or relapsed pediatric solid tumors. These investigators found that all of seven patients achieved primary engraftment, but secondary graft rejection was observed in one patient. The incidence of acute grades II–III GVHD was two (29%) cases and chronic GVHD was observed in five (83%) of six evaluable patients. Three patients underwent donor lymphocyte infusion (DLI) for tumor progression. The 2-year probability of OS was 71.4% with no TRM. These data suggest an extension of disease indications and allow for the performance of successful haploidentical transplant to treat both hematologic malignancies and other diseases, such as solid tumors and nonmalignant diseases.23
IMMUNE RECONSTITUTION AFTER UNMANIPULATED HAPLOIDENTICAL TRANSPLANTATION The recovery of different immune cell subsets after unmanipulated haploidentical transplant occurs at different rates.17,22,37– 41 The first 90 days after transplantation are characterized by persistent CD4⫹ and CD4⫹ naïve T-cell lymphopenia, which may lead to a higher cumulative incidence of cytomegalovirus (CMV) antigenemia. This renders the patient especially susceptible to viral and fungal infections. However, in our transplant protocol, compensatory expansion of monocytes and cytotoxic T lymphocytes (CTL), especially CMV-pp65 peptide-specific CTLs (CTLCMV) 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 with CMV antigen and may contribute to a reduced incidence of CMV disease.37 The expansion of memory T cells, especially CD4⫹ memory T cells that reconstitute later than CD8⫹ memory T cells and rely more on thymic production of naive T cells, results in a significant inversion of the CD4/CD8 ratio up to 1 year following transplant. An interesting finding is that T cells of patients without GVHD were equally functional in the two patient groups at day 30 after transplantation,17 although Fu et al showed that T-cell receptor rearrangement excision DNA circle (TREC) levels remain low from 12 to 24 months after haploidentical transplant.40 Rapid recovery of natural killer (NK) cells after HSCT is based on an expansion of the cytokine-producing CD56bright NK cell subset. The absolute number of overall NK cells recovered to the donors’ level by day
Reference Myeloablative regimens Symons et al, 201170
Kaida et al, 201133
Sizemore et al, 201171 Santarone et al, 201172
Huang et al, 201229
Pts (no.)
Median (range) Age, yr
30
43 (2–64)
351
20 40
21
GHVD Disease
Grafts
AML/ALL/CML/ BM NHL/HD
39 (16–65) AML/ALL/MDS/ NA ML/others
44 (25–56) AML/ALL/CML/ G-PB CLL/NHL/HD 32 (12–63) AML/ALL/CML/ G-BM NHL/PL
24 (14–56) AML/ALL/CML/ G-PB MDS/NHL
Conditioning Regimens
Bu/Cy (n ⫽ 27) Cy/TBI (n ⫽ 3)
GVHD Prophylaxis
Cy/MMF/Tac
Acute Acute II–IV III–IV Chronic
14%
TRM
Relapse
LFS
OS
7.3%
13% at 1 yr
12% at 100 d
NA
NA
NA
66% for poor-risk 23.5% at 1 yr 40% at 1 yr pts 13% for pts in CR NA NA 30% at 5 yr
Flu/Ara-C/Cy/TBI (haplo-full) MTX/MMF/Tac/mPSL 36% (n ⫽ 100) Flu/ATG/Mel or Bu 20% (haplo-mini) (n ⫽ 251) Flu/Bu/Cy Cy/MMF/Tac 30%
NA
NA
NA
NA
NA
40% at 5 yr
20%
10% at 1 yr
NA
51% at 1 yr
74% at 1 yr
NA
3%
42% at 1 yr 13%
45% at 1 yr
NA
Bu/Cy⫹ATG (n ⫽ 14)
ATG/CSA/MTX/MMF/ 23% Basiliximab
CSA/MTX/MMF
33.3% NA
CSA/MTX
20%
39.5% at 2 yr
22% for early stage 20% 35% for advanced stage 20.5% at 2 yr
25.8% at 2 yr
55.6% at 2 yr 62.1% at 2 yr
AL pts in CR1: 27% AL pts in CR2/ CR3: 32% Pts with refractory AL: 79% Pts with MDS: 20% 5/7
60%
60%
53%
41%
9%
9%
53%
53%
2/7
71.4% at 2 yr 41% at 3 yr
Haploidentical BMT without T-cell depletion
Table 1. Selected Published Studies of Unmanipulated Haploidentical Stem Cell Transplantation
TBI/Cy⫹ATG (n ⫽ 6) Nonmyeloablative regimens 83 Lee et al, 20119
Sano et al, 2011 36 Munchel et al, 201131
40 (16–70) AML/ALL/MDS
7
Pediatric
210
52 (1–73)
Solid tumors
G-PB
G-PB/ BM AML/ALL/MDS/ BM other malignancies
Bu/Flu/ATG
Flu/Mel/ATG
MTX/Pred/Tac
Flu/Cy/TBI
Cy/MMF/Tac
7%
34%
18%
2/7
1/7
5/6
0%
27%
5%
13%
18%
55%
32% at 3 yr
Abbreviations: Pts, patients; No., number; yr, year; GVHD, graft-versus-host disease; TRM, transplant-related mortality; LFS, leukemia-free survival; OS, overall survival; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myeloid leukemia; NHL, non-Hodgkin lymphoma; HD, Hodgkin disease; BM, bone marrow; Bu, busulfan; Cy, cyclophosphamide; TBI, total body irradiation; MMF, mycophenolate mofetil; Tac, tacrolimus; NA, not available; CR, complete remission; MDS, myelodysplastic syndrome; ML, malignant lymphoma; Flu, fludrabine; Ara-C, cytosine arabinoside; ATG, anti-human thymocyte immunoglobulin; Mel, melphalan; mPSL, methylprednisolone; G-PB, granulocyte colony-stimulating factor–mobilized peripheral blood stem cell grafts; PL, plasma cell leukemia; G-BM, granulocyte colony-stimulating factor–primed bone marrow; AL, acute leukemia; Pred, prednisolone.
655
G-BM⫹G-PB G-PB or BM BM G-BM⫹G-PB Malignant diseases (481) Malignant diseases (327) Malignant diseases (212) Malignant diseases (23) Huo et al, 201145 Kanda et al, 201169 Kasamon et al, 201126 Lu et al, 201141
G-BM⫹G-PB G-BM⫹G-PB Malignant diseases (348) Malignant diseases (41) Chang et al, 200943 Zhao et al, 200921
Abbreviations: No., number; BM, bone marrow; NIMA, noninherited maternal antigen; GVH, graft-versus-host; aGVHD, acute graft-versus-host disease; G-BM, granulocyte colony-stimulating factor–primed bone marrow; G-PB, granulocyte colony-stimulating factor–mobilized peripheral blood stem cell grafts; KIR, killer-cell immunoglobulin-like receptor; TRM, transplant-related mortality; LFS, leukemia-free survival; OS, overall survival; NK, natural killer; ALC30, absolute lymphocyte counts on day 30 after transplantation; HLA, human leukocyte antigen; PFS, progression- free survival. *Missing ligands are defined as absence in the recipient of one or more HLA ligands for inhibitor KIR.
Decreased risk for grade III/IV aGVHD Less TRM, improved LFS and OS Increased acute GVHD and relapse, and decreased OS. Improved LFS Decreased incidence of III–IV aGVHD and TRM, increased OS Better LFS and OS, less relapse, and less TRM Increased incidence of II–IV aGVHD Increased incidence of chronic GVHD Faster platelet engraftment Increased incidence of II–IV aGVHD Decreased incidence of III–IV aGVHD and TRM, increased OS Increased incidence of III–IV aGVHD and TRM, decreased LFS, and OS Increased TRM, and decreased OS Superior PFS Increased incidence of II–IV aGVHD NIMA mismatch in the GVH direction Two or three KIR ligands in recipients KIR ligand mismatch Day 14 CD56bright NK cells CD4/CD8 in G-BM (⬍1.16) ALC30 (ⱖ300l/L) CD4⫹CD45RA⫹CD62L⫹ cells in allografts (⬎0.22⫻108/kg) CD4⫹CD45RA⫹ cells in allografts (⬎0.45⫻108/kg) CD34⫹ cells in allografts (⬎2.19⫻108/kg) CD56bright NK cells in allografts (⬎1.9⫻106/kg) CD56dim/CD56bright NK cell ratio (⬎8.0) in allografts HLA-B-mismatch HLA-B-antigen-mismatch Missing ligands* CD4⫹CD25highCD45RA⫹CD62L⫹ T cells in allografts (⬍3.0⫻106/kg) BM G-BM⫹G-PB G-BM⫹G-PB G-BM⫹G-PB G-BM⫹G-PB G-BM⫹G-PB G-BM⫹G-PB Malignant diseases (35) Malignant diseases (64) Malignant diseases (116) Malignant diseases (43) Malignant diseases (141) Malignant diseases (206) Malignant diseases (31) Ichinohe et al, Zhao et al, 200722 Huang et al, 200719 Chang et al, 200839 Luo et al, 200942 Chang et al, 200916 Chang et al, 200944
Potential Effects on Clinical Outcomes Factors Allografts Disease (no. of patients)
Several retrospective studies have evaluated factors associated with clinical outcomes following unmanipulated haploidentical transplantation (Table 2).10,15,16,18 –22,39,42– 44 A higher CD34⫹ cell dose is associated with faster platelet engraftment both in adult and pediatric patients after haploidentical transplant without in vivo T-cell depletion.15,43 Using their unmanipulated haploidentical blood and marrow transplant protocol, the Peking University group found that a higher dose of CD4⫹CD45RA⫹CD62L⫹ or CD56bright NK cells correlated with an increased incidence of grades II–IV acute GVHD while, conversely, a lower dose of CD4⫹CD25highCD45RA⫹ CD62L⫹ T cells in the allografts was associated with a higher incidence of grades II–IV acute GVHD.21,44 Other factors, including a lower CD56dim/CD56bright NK cell ratio (⬍8.0) and a higher CD4/CD8 ratio (⬎1.16) in the allografts, may contribute not only to higher risk of acute GVHD but also to increased TRM and decreased OS.21,42 Recently, Huo et al45 reported that HLA-B mismatch was an independent risk factor for acute GVHD and TRM after HLA-haploidentical transplantation without ex vivo TCD. Researchers from Japan also showed that among patients with standard-risk diseases who received transplantation from a related donor with an HLA-1 antigen mismatch at the HLA-A, HLA-B, or HLA-DR loci in the graft-versus-host direction, the presence of an HLA-B antigen mismatch was significantly associated with a lower OS rate. In contrast, Kasamon et al10 and Lee et al9 failed to find a detrimental effect of HLA disparity on clinical outcomes after unmanipulated haploidentical transplantation using RIC. Lee et al9 suggest that the disparities in major histocompatibility complex (MHC) genes as determinants of adverse
200413
FACTORS INFLUENCING OUTCOMES FOLLOWING UNMANIPULATED HAPLOIDENTICAL TRANSPLANTATION
Reference
30 in patients who never developed GVHD. Patients with more CD56bright NK cells in the recovery stage had a higher survival rate.22,38,39 The reconstitution of killercell immunoglobulin-like receptors (KIR) after unmanipulated haploidentical transplantation recently has been reviewed in detail elsewhere. Reconstitution of B cells and monocytes is comparable between haploidentical transplant recipients versus HLA-matched recipients.17 Compared with MSD transplantation, the early reconstitution of myeloid dendritic cell 1 (MDC1), MDC2, and plasmacytoid dendritic cells was significantly delayed after haploidentical transplantation. Considering the early delayed immune reconstitution following unmanipulated haploidentical transplantation, strategies to improve immune recovery or posttransplantation vaccination should be investigated further.
Y.-J. Chang and X.-J. Huang
Table 2. Factors Associated With Clinical Outcomes Following Unmanipulated Haploidentical Stem Cell Transplantation
656
Haploidentical BMT without T-cell depletion
outcomes of HSCT may be less important when a RIC regimen containing anti–T-cell agents is used. Moreover, the low level of HLA gene heterogeneity observed in Korean patients may contribute to the favorable outcomes of HLA-haploidentical HSCT. However, these reasons cannot explain why HLA disparity does not appear to worsen OS after nonmyeloablative haploidentical BMT with high-dose post-transplantation Cy reported by the Baltimore group.10 Hence, further studies are necessary to elucidate the underlying mechanisms. The association of immune reconstitution with clinical outcomes, such as infection rates, TRM, or survival, has been confirmed both in HLA-matched sibling and unrelated donor transplant settings.46 In our transplant protocol, we found that early lymphocyte recovery correlates with superior survival.16 Chang et al39 also showed a survival advantage for patients with high early levels of CD56bright NK cells (day 14 CD56bright NK cells) after unmanipulated haploidentical transplantation. This result was recently confirmed by a Spanish group, using unmanipulated haploidentical bone marrow grafts after RIC.38 The association of alloreactive NK cells and transplantation outcomes of patients undergoing unmanipulated haploidentical transplantation has been recently reviewed in detail elsewhere.47,48 In summary, prospective studies with larger series of patients are needed to draw definitive conclusions on the impact of cell composition, HLA matching, and other factors in the T-cell–replete (TCR) nonmyeloablative or myeloablative haploidentical settings. These studies are necessary and important for predicting clinical outcomes such as infection rates, GVHD, and TRM and developing new methods for improving survival.
COMPARISON OF OUTCOMES BETWEEN UNMANIPULATED HAPLOIDENTICAL TRANSPLANT AND OTHER TRANSPLANT PROTOCOLS Several researchers have published retrospective studies highlighting the differences in unmanipulated haploidentical transplant versus HLA-matched sibling donor (MSD) transplantation, MUD transplantation, or unrelated double umbilical cord blood (dUCB) transplantation (Table 3). Lu et al49 found that leukemia-free survival and OS were comparable following unmanipluated haploidentical transplant and MSD transplantation, although unmanipulated haploidentical transplant was characterized by delayed early reconstitution of T cells and dendritic cells, as well as a higher incidence of CMV antigenemia. Several reasons may account for this finding: (1) compensatory expansion of monocytes and cytotoxic CD8⫹ lymphocytes17; (2) pre-emptive management of CMV antigenemia; (3) superior graft-versusleukemia effects associated with transplantation of haplo-identical compared with HLA-identical sibling do-
657
nor grafts for high-risk AL50; and (4) improvements in pharmacoprophylaxis of GVHD and supportive care. The same group also showed that for every major HSCT end point, including relapse, nonrelapse mortality, and survival, partially matched related and unrelated HSCT are not significantly different.51 The above-mentioned results also were demonstrated by Liu et al25 and Valcarcel et al,52 but in a multicenter study, Shaw et al53 showed that single HLA-mismatched related donor and MUD outcomes are similar, whereas HLA-MSD outcomes are superior. The Blood and Marrow Transplant Clinical Trials Network (BMTCTN) performed two independent, multicenter, phase II studies evaluating the outcomes of dUCBT and haploidentical BMT.54 Patients in these two treatment groups had similar eligibility criteria and used a similar nonmyeloablative conditioning regimen. One-year cumulative incidences of TRM and relapse were 24% and 31% after dUCBT and 7% and 45% after haploidentical transplantation, respectively. One-year OS and EFS were 54% and 46% after dUCBT and 62% and 48% after haploidentical transplantation, respectively. As two independent phase II studies,54 the results cannot be compared directly. Further investigation is required to directly compare the results of hematopoietic transplantation from different donor sources, including UCB, MSD, MUD, and haploidentical donors. Researchers from M.D. Anderson Cancer Center reported an interesting comparative study. Ciurea et al55 showed that patients who received TCR haploidentical transplants had better OS (66% v 30%, P ⫽ .02) and progression-free survival (45% v 21%, P ⫽ .03) at 1 year post-transplant compared with those who underwent TCD haploidentical transplantation. The investigators also found that improved transplant outcomes in the TCR group were related to significantly better immunologic reconstitution of T-cell subsets. They showed that CD4⫹ T cells recovered at day 180 following transplantation were significantly lower in the TCD group than those in the TCR group (64/L v 200.5/L, P ⫽ .04). These data warrant a randomized, prospective study to elucidate the superiority of unmanipulated transplantation compared to CD34-selected transplantation in the haploidentical setting.
STRATEGIES TO IMPROVE TRANSPLANT OUTCOMES AFTER UNMANIPULATED HAPLOIDENTICAL TRANSPLANT Currently, unmanipulated transplant represents a strategy in haploidentical settings that does not require the technical expertise and cost of ex vivo T-cell depletion. However, delayed platelet engraftment, high risk of relapse (after nonmyeloablative regimens) following transplantation, and early delayed immune reconstitution remain major limitations of unmanipulated
658
Table 3. Comparison of Unmanipulated Haploidentical Transplantation With HLA-Matched Related or Unrelated or Unrelated dUCB Transplantation Shaw et al, 201153 Multicenter Clinical Trial
No. of patients Age (yr) Sex, male/female, no. Dianosis AML ALL CML MDS Others Donor-recipient match 0 Mismatch 1 Mismatch 2 Mismatch 3 Mismatch Conditioning regimen
GVHD prophylaxis
MSD
mmRD
MUD
PMRD
MUD
1,208 9 (⬍1–17) 729/479
151 8 (⬍1–17) 96/55
266 9 (⬍1–17) 162/124
219 25 (5–53) 138/81
78 30 (10–49) 52/26
42 67 23 19 0
67 136 26 37 0
447 559 97 105 0
67 72 61 19 0
1,208 0 0 0 TBI-based regimen (47%) ATG-based regimen (99%) CSA/FK506⫾MTX (79%) CSA/FK506⫾others (21%)
0 151 0 0 TBI-based regimen (43%) ATG-based regimen (81%) CSA/FK506⫾MTX (85%) CSA/FK506⫾others (15%)
266 0 0 0 TBI-based regimen (20%) ATG-based regimen (81%) CSA/FK506⫾MTX (94%) CSA/FK506⫾others (6%)
0 27 87 105 Bu/Cy/ATG/MeCCNU ⫹Ara-C (4 g/m2/ d⫻2d) CSA/MTX/MMF
NA NA
NA NA
NA NA
7.2 (3.4–21) 2.2 (0.7–7.1)
NA
NA
NA
170 (10–830)
NA NA
NA NA
NA NA
13 (9–24) 15 (7–140)
29% (26–31) at d100 15% (13–17) at 1 yr 79 (2–171)
56% (48–64) at d100 30% (23–38) at 1 yr 62 (2–177)
45% (39–51) at d100 33% (27–39) at 1 yr 61 (12–168)
36% (33–39) at 3 yr
29% (22–37) at 3 yr
32% (27–38) at 3 yr
Brunstein et al, 201154 Multicenter Clinical Trial Unrelated dUCB 50 58 (16–69) NA
25 18 32 3 0
61 16 1 0 Bu/Cy/ATG/MeCCNU ⫹Ara-C (2 g/m2/ d⫻2d) CSA/MTX/MMF
Wang et al, 201150 Single-Center Clinical Trial
HID
MSD
HID
50 48 (7–70) NA
36 41 (15–56) 27/9
81 29 (5–50) 52/29
29 6 0 0 15
22 6 0 0 22
20 16 0 0 0
3 14 33 0 Flu/Cy/TBI (n ⫽ 50)
1 (8 of 10) 9 (7 of 10) 12 (6 of 10) 28 (5 of 10) Flu/Cy/TBI (n ⫽ 50)
MMF/CSA
MMF/CSA/ FK506/Cy
5.9 (1.7–15) 2.8 (0.8–10.6)
4.2 (3.1–16.3) NA
NA NA
6.8 (4.0–14) 2.5 (1.1–3.6)
7.1 (3.6–11) 2.9 (1.5–6.2)
220 (130–410)
NA
NA
190 (70–390)
180 (70–940)
16 (15–21) 15 (7–100)
13 (9–29) 15 (7–74)
12 (9–20) 13 (4–85)
15 (4–47) 43 (29–323)
16 (12–83) 24 (1–92)
47% (39–62) at d100 54% (47–61) at 2 yr 23 (0.3–60)
31% (20–42) at d100 40% (31–52) at 2 yr 22 (0.7–60)
12% (8–16) at 2 yr
18% (10–27) at 2 yr
40% (26–54) at d100 25% (12–39) at 1 yr 365 (56–411) days 31% (17–44) at 1 yr
32% (19–45) at d100 13% (3–23) at 1 yr 357 (103–441) days 45% (30–61) at 1 yr
36 0 0 0 Bu/Cy/ATG/MeCCNU ⫹Ara-C (4 g/m2/ d⫻2d) CSA/MMF/MTX
30 51 0 0 0
0 7 20 54 Bu/Cy/Hu/MeCCNU ⫹Ara-C (2 g/m2/ d⫻2d) CSA/MMF/MTX
24% (9–41) at d100 39% (20–58) at 2 yr 11 (0.6–46)
49% (37–61) at at d100 62% (49–75) at 2 yr 16 (0.8–59)
49% (31–67) at 2 yr
26% (15–37) at 2 yr
Y.-J. Chang and X.-J. Huang
Cell dose median TNC (⫻108/kg) CD34⫹ cells (⫻106/kg) CD3⫹ cells (⫻106/ kg) Engraftment (days) ANC engraftment PLT engraftment GVHD aGVHD IHV (% Cum. Incid.) cGVHD (% Cum. Incid.) Median follow-up (mo) Relapse (% Cum. Incid.)
Huang et al, 200951 Single-Center Clinical Trial
All values are given as median (% or range), unless otherwise specified. Abbreviations: HLA, human leukocyte antigen; dUCB, double umbilical cord blood; MSD, matched sibling donors; mmRD, mismatched related donors; MUD, matched unrelated donors; PMRD, partially matched related donors; HID, haploidentical donors; NA, not available; AML, acute myeloid leukemia; ALL, acute lymphoid leukemia; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome; Bu, busulfan; Cy, cyclophosphamide; ATG, anti-thymocyte globulin; TBI, total body irradiation; Ara-C, cytosine arabinoside; Me-CCNU, semustine; Hu, hydroxycarbamide; GVHD, graft-versus-host disease; CSA, cyclosporine A; FK506, tacrolimus; MTX, methotrexate; MMF, mycophenolate mofetil; TNC, total nuclear cells; ANC, absolute neutrophil count; PLT, platelet; TRM, transplant-related mortality; LFS, leukemia-free survival; OS, overall survival; Cum. Incid., cumulative incidence.
OS (% Cum. Incid.)
HID
34% (22–46) at 2 yr 42% (30–54) at 3 yr 42% (30–54) at 3 yr 38% (21–55) at 2 yr 15% (1–29) at 3 yr 20% (4–36) at 3 yr
MSD HID
7% (0–15) at 1 yr 48% (32–62) at 1 yr 62% (44–76) at 1 yr 24% (11–36) at 1 yr 46% (31–60) at 1 yr 54% (38–67) at 1 yr 18% (10–28) at 2 yr 61% (47–74) at 4 yr 74% (62–86) at 4 yr 20% (15–26) at 2 yr 67% (59–75) at 4 yr 74% (68–80) at 4 yr 24% (19–30) at 3 yr 43% (37–49) at 3 yr 32% (27–38) at 3 yr 2% (20–34) at 3 yr 44% (36–53) at 3 yr 29% (22–37) at 3 yr
Unrelated dUCB MUD PMRD MUD mmRD MSD
10% (8–12) at 3 yr 54% (51–57) at 3 yr 61% (58–64) at 3 yr TRM (% Cum. Incid.) LFS (% Cum. Incid.)
Table 3. Continued
Shaw et al, 201153 Multicenter Clinical Trial
Huang et al, 200951 Single-Center Clinical Trial
Brunstein et al, 201154 Multicenter Clinical Trial
Wang et al, 201150 Single-Center Clinical Trial
Haploidentical BMT without T-cell depletion
659
haploidentical HSCT. Thus, several strategies are being developed to improve clinical outcomes following haploidentical transplantation without ex vivo T-cell depletion.
Co-transplantation of Mesenchymal Stem Cells to Optimize Stem Cell Engraftment In adult patients undergoing transplantation from an HLA-identical sibling, mesenchymal stem cell (MSC) infusion was shown to be safe and possibly to accelerate hematopoietic recovery, as well as reduce the incidence of both acute and chronic GVHD.56 Ball et al2 cotransplanted donor-derived MSCs in 14 children undergoing TCD haploidentical transplantation. None of the patients given MSCs experienced either an adverse reaction or graft failure. The sustained donor engraftment observed in patients treated with MSCs compared favorably with the risk of rejection observed in haploidentical HSCT recipients, which has been reported in various studies to be 10%–20%.2 Recently, we conducted an open-label, randomized phase II clinical study to assess the outcome of MSC co-infusion (3– 5⫻105 cells/kg) during unmanipulated haploidentical HSCT.57 No immediate or long-term toxic side effects related to MSC infusion were observed. Within 100 days, the time to platelet concentration of ⬎50⫻109 cells/L was markedly faster in the treatment group compared with the control group (22 days v 28 days; P ⫽ .036). The cumulative occurrence of GVHD, relapse, leukemia-free survival, and OS were comparable between the treatment and control groups. The results reported by Ball et al2 and by our group57 suggest that co-transplantation of hematopoietic progenitors and MSCs may modulate host alloreactivity and/or promote better engraftment of donor hematopoiesis, reducing the risk of early graft failure when HLA disparity is present in the donor/recipient pair. The mechanisms may be related to higher concentrations of stromal cell– derived factor-1␣ (SDF-1␣), thrombopoietin, and interleukin-11.57
G-CSF–Primed DLI to Decrease Relapse In previous studies, we administered G-CSF–primed DLI prophylactically to 29 patients and therapeutically to 20 patients. Two-year EFS was 37.3% for recipients of prophylactic DLI and 40% after therapeutic DLI.58,59 These preliminary data suggest that G-CSF–primed DLI is safe and effective for both prophylaxis against relapse and treatment of recurrence after unmanipulated haploidentical transplantation. In a retrospective study,60 we analyzed the data of 88 patients with advanced-stage AL after unmanipulated haploidentical HSCT whose treatment did (n ⫽ 61) or did not (n ⫽ 27) include G-CSF–primed DLI. The 2-year cumulative incidences of relapse in patients receiving prophylactic DLI versus not receiving prophylactic DLI were 36%
660 and 55% (P ⫽ .017), respectively. Estimated OS and EFS at 3 years were 31% and 22%, respectively, for patients receiving prophylactic DLI, and 11% and 11%, respectively, for patients not receiving prophylactic DLI (P ⫽ .001 and .003, respectively). Multivariate analysis showed that use of prophylactic DLI after transplantation was an independent prognostic factor for relapse. Higher OS was associated with use of prophylactic DLI, acute myeloid leukemia, and female sex.60 Our results further suggest that use of prophylactic DLI may increase survival of patients with advanced-stage AL who receive HLA-mismatched/haploidentical HSCT. For acute lymphocytic leukemia patients receiving allografts from haploidentical donors, other methods should be investigated to decrease relapse and improve transplant outcomes. Further study to investigate the dose-response relationships for both GVHD and antitumor efficacy are clearly required before DLI can be routinely recommended for the prevention or treatment of relapse after unmanipulated haploidentical HSCT.
Methods to Enhance Immune Reconstitution After Unmanipulated Haploidentical Transplantation Regulatory T cells (Tregs) play a key role in the prevention and treatment of acute GVHD after allogeneic BMT in murine models.61 In recent clinical trials, the infusion of Tregs after haploidentical62 and UCB63 stem cell transplantation to prevent GVHD and promote immune reconstitution has produced promising results. The Peking University group41 found that that a large population of CD62L⫹ naive Tregs (CD4⫹CD25highCD45RA⫹CD62L⫹ T cells) in allografts reduces the incidence of acute GVHD. Further, development of acute GVHD is related closely to the delayed reconstitution of the naive Treg population. Taken together, these data suggest that a clinical trial should be designed to evaluate the effects of Tregs on acute GVHD prevention and immune recovery promotion in haploidentical HSCT settings without ex vivo T-cell depletion. In unmanipulated haploidentical transplant settings, we found early delayed immune reconstitution, although CD4⫹ cells recovered to nearly 200/L at day 180 after transplantation.17,55 Therefore, recombinant interleukin-2 was administered as a consolidating immunotherapeutic agent early after HSCT at a time of minimal residual disease, which may reduce the relapse rate and increase the immunocompetence of these patients.64 This could be because of a lymphoid orientation of primitive CD34⫹CD105⫹ cells, which express high-affinity interleukin-2 receptors. Exogenous interleukin-2 might thus lead to an enhancement of the graft-versus-leukemia (GVL) effect.64,65 Our findings also support that measuring levels of CTLCMV and its
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subsets in the donor grafts and manipulating these cells early after transplantation may help control CMV reactivation, which correlates closely with immune reconstitution and differentiation of CTLCMV subsets.66 To improve clinical outcomes, novel strategies to enhance immune reconstitution after unmanipulated haploidentical HSCT should be explored in the future.67,68
FUTURE DIRECTIONS Over the past several years, unmanipulated haploidentical transplantation has been adopted by more and more transplant centers worldwide.6,7,9,10,33–38,69 –72 The advantages of haploidentical donors without TCD as a stem cell source are: (1) absence of the technical expertise and cost of ex vivo T-cell depletion6,8; (2) high T-cell content of allografts potentially enhances the GVL effect50; and (3) accelerated immune reconstitution compared with CD34-selected haplotype-mismatched transplants.37 The disadvantages of unmanipulated haploidentical transplant include: (1) potentially severe GVHD induced by T cells6,8; and (2) a high incidence of leukemia relapse for patients receiving reduced-intensity protocols.31 Considering the advantages and disadvantages of haploidentical donor without TCD and the fact that different conditioning regimens, different GVHD prophylaxis, and different stem cell grafts were used by different transplant groups,10,12–14,23,31,49,54 the kinetics of immune reconstitution, and factors associated with clinical outcomes should be investigated at different transplant centers to improve survival. Currently, TCR and TCD HSCT represent two main transplant protocols in haploidentical transplant settings.6,8 However, we cannot promote a definitive strategy for haploidentical transplant protocol selection because each has its own advantages and disadvantages. Therefore, prospective randomized comparative studies and clinical trial participation is encouraged. In addition, future randomized studies will be required to compare UCB, haploidentical donor, and mismatched unrelated donor to more conventional related and MUD sources. It is reasonable that the above-mentioned studies will allow us to make individual therapeutic choices for patients in the future.
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56. Lazarus HM, Koc ON, Devine SM, et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant. 2005;11:389 –98. 57. Liu K, Chen Y, Zeng Y, et al. Coinfusion of mesenchymal stromal cells facilitates platelet recovery without increasing leukemia recurrence in haploidentical hematopoietic stem cell transplantation: a randomized, controlled clinical study. Stem Cells Dev. 2011;20:1679 – 85. 58. Huang XJ, Liu DH, Liu KY, et al. Modified donor lymphocyte infusion after HLA-mismatched/haploidentical T cell-replete hematopoietic stem cell transplantation for prophylaxis of relapse of leukemia in patients with advanced leukemia. J Clin Immunol. 2008;28:276 – 83. 59. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W. Donor lymphocyte infusion for the treatment of leukemia relapse after HLA-mismatched/haploidentical T-cell-replete hematopoietic stem cell transplantation. Haematologica. 2007;92:414 –7. 60. Wang Y, Liu DH, Xu LP, et al. Prevention of relapse using granulocyte CSF-primed PBPCs following HLA-mismatched/haploidentical, T-cell-replete hematopoietic SCT in patients with advanced-stage acute leukemia: a retrospective risk-factor analysis. Bone Marrow Transplant. 2012;47:1099 –104. 61. Boeld TJ, Doser K, Lang-Schwarz C, et al. Efficient treatment of murine acute graft-versus-host disease with in vitro expanded CD4⫹CD25⫹ regulatory T cells. Blood. 2011;118:abstract 2987. 62. Di Ianni M, Falzetti F, Carotti A, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117:3921– 8. 63. Brunstein CG, Miller JS, Cao Q, et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood. 2011;117:1061–70. 64. Liu KY, Chen YH, Liu DH, Xu LP, Huang XJ. A pilot study of low-dose recombinant interleukin-2 for acute lymphoblastic malignancy after unmanipulated allogeneic blood
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H
aploidentical/mismatched bone marrow transplantation (BMT) offers the benefits of rapid and near universal donor availability and has been accepted worldwide as an alternative treatment for patients with hematologic malignancies who do not have a human leukocyte antigen (HLA) completely matched sibling or who require urgent transplantation.1–26 Several transplant centers reported success with transplantation of T-cell–depleted (TCD) peripheral blood stem cells (PBSC) with a low rate of graftversus-host disease (GVHD), but these transplants are associated with a high rate of rejection, slow immune reconstitution, and a substantial risk of treatment-related mortality (TRM).1,8,27–29 Therefore, many centers actively pursue BMT without T-cell depletion using unmanipulated haploidentical transplant protocols.5–7,9,30,31 The approaches used include anti-thymocyte globulin (ATG) preparative regimens for partial in vivo T-cell depletion, granulocyte colony-stimulating factor–primed grafts to Peking University People’s Hospital, Peking University Institute of Hematology, Beijing, China. The authors report no potential conflicts of interest. Address correspondence to Xiao-Jun Huang, MD, Peking University People’s Hospital, No. 11 Xizhimen South St, Beijing 100044, China. E-mail: [email protected] 0270-9295/ - see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2012.09.003
polarize the T-cell response to a TH-2 type pattern, posttransplantation rapamycin to favor development of regulatory T-cell populations, or high-dose post-transplant cyclophosphamide (Cy) to preferentially deplete alloreactive T cells. Preliminary results of haploidentical hematopoietic stem cell transplantation (HSCT) employing myeloablative or nonmyeloablative conditioning regimens followed by infusion of unmanipulated stem cell grafts have been published.12–14,32 Over the past several years, results of unmanipulated haploidentical HSCT have substantially improved due to enhanced GVHD prophylaxis, the development of new conditioning regimens, novel strategies for relapse prophylaxis, and improved supportive care. The objective of this review is to provide up-to-date data on long-term follow-up results, immune reconstitution, factors associated with clinical outcomes, and strategies to improve outcomes after unmanipulated haploidentical HSCT.
CURRENT STATUS OF UNMANIPULATED HAPLOIDENTICAL TRANSPLANTATION Recently, long-term follow-up results were reported by researchers from transplant centers in the United States, Japan, China, and elsewhere. At Johns Hopkins University, 210 patients with hematologic malignancies who received nonmyeloablative, HLA-haploidentical transplantation with high-dose, post-transplantation Cy
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were retrospectively analyzed (Table 1). Munchel et al31 found that the cumulative incidences of grades II–IV acute GVHD and chronic GVHD were 27% and 13%, respectively. The cumulative incidences of relapse and non-relapse mortality were 55% and 18%, respectively. Three-year overall survival (OS) and eventfree survival (EFS) were 41% and 32%, respectively. At Hyogo College of Medicine (Japan), Kaida et al33 summarized 351 cases of haploidentical stem cell transplantation. Among them, 100 patients underwent a myeloablative preconditioning regimen (haplo-full) and 251 patients received a reduced-intensity conditioning (RIC) regimen (haplo-mini). Acute GVHD (grades II–IV) was observed in 36 % for haplo-full and 20% for haplomini, respectively. OS at 5 years was 30% for haplo-full and 40% for haplo-mini. Multivariate analysis showed that disease status (complete remission [CR]) was the significantly favorable variable (P ⫽ .0026). At Pusan National University (Korea), Lee et al9 assessed 83 patients enrolled in haploidentical transplant trials using RIC with busulfan, fludarabine, and ATG. The cumulative incidences of neutrophil engraftment, grades II–IV acute GVHD, chronic GVHD, and TRM after HSCT were 92%, 20%, 34%, and 18%, respectively. After a median follow-up time of 26.6 months (range, 16.8 – 78.8 months), EFS and OS rates were 56% and 45%, respectively, for patients with acute leukemia (AL) in remission; 9% and 9%, respectively, for patients with refractory AL; and 53% and 53%, respectively, for patients with myelodysplastic syndrome. At Peking University, from May 2002 to December 2010, 820 patients with hematologic malignancies, including 206 in the high-risk group, received transplantation from haploidentical family donors without T-cell depletion. Eight hundred eleven patients (99%) achieved sustained, full donor chimerism. The incidence of grades II–IV acute GVHD was 42.9%, and that of grades III–IV was 14.0%, which was not associated with the extent of HLA disparity. EFS rates for low- and high-risk patients were nearly 45% and 70%, respectively.34 Taken together, long-term follow-up results from different transplant centers suggest unmanipulated transplant may provide an alternative strategy in the haploidentical setting without requiring the technical expertise and cost of ex vivo T-cell depletion as compared with TCD haploidentical transplant. More recently, Muramatsu et al35 reported 53 pediatric patients with aplastic anemia (AA) who underwent unmanipulated haploidentical transplantation. They found that the probability of grades III–IV acute GVHD in patients transplanted from a one locus-mismatched related donor (1MMRD) was significantly higher than that in patients transplanted from an HLAmatched related donor (MRD) (P ⬍.001). The probability of 5-year OS of patients transplanted from 1MMRD was comparable to that of patients transplanted from a MRD, but it was significantly better than
Y.-J. Chang and X.-J. Huang
that of patients transplanted from two to three locimismatched related donors and HLA-matched unrelated donor (MUD). These data reveal that an HLAmismatched related donor, especially 1MMRD, could be an acceptable donor candidate for children with AA requiring urgent transplantation. Sano et al36 have extended non–TCD HLA haploidentical stem cell transplantation to treat refractory or relapsed pediatric solid tumors. These investigators found that all of seven patients achieved primary engraftment, but secondary graft rejection was observed in one patient. The incidence of acute grades II–III GVHD was two (29%) cases and chronic GVHD was observed in five (83%) of six evaluable patients. Three patients underwent donor lymphocyte infusion (DLI) for tumor progression. The 2-year probability of OS was 71.4% with no TRM. These data suggest an extension of disease indications and allow for the performance of successful haploidentical transplant to treat both hematologic malignancies and other diseases, such as solid tumors and nonmalignant diseases.23
IMMUNE RECONSTITUTION AFTER UNMANIPULATED HAPLOIDENTICAL TRANSPLANTATION The recovery of different immune cell subsets after unmanipulated haploidentical transplant occurs at different rates.17,22,37– 41 The first 90 days after transplantation are characterized by persistent CD4⫹ and CD4⫹ naïve T-cell lymphopenia, which may lead to a higher cumulative incidence of cytomegalovirus (CMV) antigenemia. This renders the patient especially susceptible to viral and fungal infections. However, in our transplant protocol, compensatory expansion of monocytes and cytotoxic T lymphocytes (CTL), especially CMV-pp65 peptide-specific CTLs (CTLCMV) 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 with CMV antigen and may contribute to a reduced incidence of CMV disease.37 The expansion of memory T cells, especially CD4⫹ memory T cells that reconstitute later than CD8⫹ memory T cells and rely more on thymic production of naive T cells, results in a significant inversion of the CD4/CD8 ratio up to 1 year following transplant. An interesting finding is that T cells of patients without GVHD were equally functional in the two patient groups at day 30 after transplantation,17 although Fu et al showed that T-cell receptor rearrangement excision DNA circle (TREC) levels remain low from 12 to 24 months after haploidentical transplant.40 Rapid recovery of natural killer (NK) cells after HSCT is based on an expansion of the cytokine-producing CD56bright NK cell subset. The absolute number of overall NK cells recovered to the donors’ level by day
Reference Myeloablative regimens Symons et al, 201170
Kaida et al, 201133
Sizemore et al, 201171 Santarone et al, 201172
Huang et al, 201229
Pts (no.)
Median (range) Age, yr
30
43 (2–64)
351
20 40
21
GHVD Disease
Grafts
AML/ALL/CML/ BM NHL/HD
39 (16–65) AML/ALL/MDS/ NA ML/others
44 (25–56) AML/ALL/CML/ G-PB CLL/NHL/HD 32 (12–63) AML/ALL/CML/ G-BM NHL/PL
24 (14–56) AML/ALL/CML/ G-PB MDS/NHL
Conditioning Regimens
Bu/Cy (n ⫽ 27) Cy/TBI (n ⫽ 3)
GVHD Prophylaxis
Cy/MMF/Tac
Acute Acute II–IV III–IV Chronic
14%
TRM
Relapse
LFS
OS
7.3%
13% at 1 yr
12% at 100 d
NA
NA
NA
66% for poor-risk 23.5% at 1 yr 40% at 1 yr pts 13% for pts in CR NA NA 30% at 5 yr
Flu/Ara-C/Cy/TBI (haplo-full) MTX/MMF/Tac/mPSL 36% (n ⫽ 100) Flu/ATG/Mel or Bu 20% (haplo-mini) (n ⫽ 251) Flu/Bu/Cy Cy/MMF/Tac 30%
NA
NA
NA
NA
NA
40% at 5 yr
20%
10% at 1 yr
NA
51% at 1 yr
74% at 1 yr
NA
3%
42% at 1 yr 13%
45% at 1 yr
NA
Bu/Cy⫹ATG (n ⫽ 14)
ATG/CSA/MTX/MMF/ 23% Basiliximab
CSA/MTX/MMF
33.3% NA
CSA/MTX
20%
39.5% at 2 yr
22% for early stage 20% 35% for advanced stage 20.5% at 2 yr
25.8% at 2 yr
55.6% at 2 yr 62.1% at 2 yr
AL pts in CR1: 27% AL pts in CR2/ CR3: 32% Pts with refractory AL: 79% Pts with MDS: 20% 5/7
60%
60%
53%
41%
9%
9%
53%
53%
2/7
71.4% at 2 yr 41% at 3 yr
Haploidentical BMT without T-cell depletion
Table 1. Selected Published Studies of Unmanipulated Haploidentical Stem Cell Transplantation
TBI/Cy⫹ATG (n ⫽ 6) Nonmyeloablative regimens 83 Lee et al, 20119
Sano et al, 2011 36 Munchel et al, 201131
40 (16–70) AML/ALL/MDS
7
Pediatric
210
52 (1–73)
Solid tumors
G-PB
G-PB/ BM AML/ALL/MDS/ BM other malignancies
Bu/Flu/ATG
Flu/Mel/ATG
MTX/Pred/Tac
Flu/Cy/TBI
Cy/MMF/Tac
7%
34%
18%
2/7
1/7
5/6
0%
27%
5%
13%
18%
55%
32% at 3 yr
Abbreviations: Pts, patients; No., number; yr, year; GVHD, graft-versus-host disease; TRM, transplant-related mortality; LFS, leukemia-free survival; OS, overall survival; AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myeloid leukemia; NHL, non-Hodgkin lymphoma; HD, Hodgkin disease; BM, bone marrow; Bu, busulfan; Cy, cyclophosphamide; TBI, total body irradiation; MMF, mycophenolate mofetil; Tac, tacrolimus; NA, not available; CR, complete remission; MDS, myelodysplastic syndrome; ML, malignant lymphoma; Flu, fludrabine; Ara-C, cytosine arabinoside; ATG, anti-human thymocyte immunoglobulin; Mel, melphalan; mPSL, methylprednisolone; G-PB, granulocyte colony-stimulating factor–mobilized peripheral blood stem cell grafts; PL, plasma cell leukemia; G-BM, granulocyte colony-stimulating factor–primed bone marrow; AL, acute leukemia; Pred, prednisolone.
655
G-BM⫹G-PB G-PB or BM BM G-BM⫹G-PB Malignant diseases (481) Malignant diseases (327) Malignant diseases (212) Malignant diseases (23) Huo et al, 201145 Kanda et al, 201169 Kasamon et al, 201126 Lu et al, 201141
G-BM⫹G-PB G-BM⫹G-PB Malignant diseases (348) Malignant diseases (41) Chang et al, 200943 Zhao et al, 200921
Abbreviations: No., number; BM, bone marrow; NIMA, noninherited maternal antigen; GVH, graft-versus-host; aGVHD, acute graft-versus-host disease; G-BM, granulocyte colony-stimulating factor–primed bone marrow; G-PB, granulocyte colony-stimulating factor–mobilized peripheral blood stem cell grafts; KIR, killer-cell immunoglobulin-like receptor; TRM, transplant-related mortality; LFS, leukemia-free survival; OS, overall survival; NK, natural killer; ALC30, absolute lymphocyte counts on day 30 after transplantation; HLA, human leukocyte antigen; PFS, progression- free survival. *Missing ligands are defined as absence in the recipient of one or more HLA ligands for inhibitor KIR.
Decreased risk for grade III/IV aGVHD Less TRM, improved LFS and OS Increased acute GVHD and relapse, and decreased OS. Improved LFS Decreased incidence of III–IV aGVHD and TRM, increased OS Better LFS and OS, less relapse, and less TRM Increased incidence of II–IV aGVHD Increased incidence of chronic GVHD Faster platelet engraftment Increased incidence of II–IV aGVHD Decreased incidence of III–IV aGVHD and TRM, increased OS Increased incidence of III–IV aGVHD and TRM, decreased LFS, and OS Increased TRM, and decreased OS Superior PFS Increased incidence of II–IV aGVHD NIMA mismatch in the GVH direction Two or three KIR ligands in recipients KIR ligand mismatch Day 14 CD56bright NK cells CD4/CD8 in G-BM (⬍1.16) ALC30 (ⱖ300l/L) CD4⫹CD45RA⫹CD62L⫹ cells in allografts (⬎0.22⫻108/kg) CD4⫹CD45RA⫹ cells in allografts (⬎0.45⫻108/kg) CD34⫹ cells in allografts (⬎2.19⫻108/kg) CD56bright NK cells in allografts (⬎1.9⫻106/kg) CD56dim/CD56bright NK cell ratio (⬎8.0) in allografts HLA-B-mismatch HLA-B-antigen-mismatch Missing ligands* CD4⫹CD25highCD45RA⫹CD62L⫹ T cells in allografts (⬍3.0⫻106/kg) BM G-BM⫹G-PB G-BM⫹G-PB G-BM⫹G-PB G-BM⫹G-PB G-BM⫹G-PB G-BM⫹G-PB Malignant diseases (35) Malignant diseases (64) Malignant diseases (116) Malignant diseases (43) Malignant diseases (141) Malignant diseases (206) Malignant diseases (31) Ichinohe et al, Zhao et al, 200722 Huang et al, 200719 Chang et al, 200839 Luo et al, 200942 Chang et al, 200916 Chang et al, 200944
Potential Effects on Clinical Outcomes Factors Allografts Disease (no. of patients)
Several retrospective studies have evaluated factors associated with clinical outcomes following unmanipulated haploidentical transplantation (Table 2).10,15,16,18 –22,39,42– 44 A higher CD34⫹ cell dose is associated with faster platelet engraftment both in adult and pediatric patients after haploidentical transplant without in vivo T-cell depletion.15,43 Using their unmanipulated haploidentical blood and marrow transplant protocol, the Peking University group found that a higher dose of CD4⫹CD45RA⫹CD62L⫹ or CD56bright NK cells correlated with an increased incidence of grades II–IV acute GVHD while, conversely, a lower dose of CD4⫹CD25highCD45RA⫹ CD62L⫹ T cells in the allografts was associated with a higher incidence of grades II–IV acute GVHD.21,44 Other factors, including a lower CD56dim/CD56bright NK cell ratio (⬍8.0) and a higher CD4/CD8 ratio (⬎1.16) in the allografts, may contribute not only to higher risk of acute GVHD but also to increased TRM and decreased OS.21,42 Recently, Huo et al45 reported that HLA-B mismatch was an independent risk factor for acute GVHD and TRM after HLA-haploidentical transplantation without ex vivo TCD. Researchers from Japan also showed that among patients with standard-risk diseases who received transplantation from a related donor with an HLA-1 antigen mismatch at the HLA-A, HLA-B, or HLA-DR loci in the graft-versus-host direction, the presence of an HLA-B antigen mismatch was significantly associated with a lower OS rate. In contrast, Kasamon et al10 and Lee et al9 failed to find a detrimental effect of HLA disparity on clinical outcomes after unmanipulated haploidentical transplantation using RIC. Lee et al9 suggest that the disparities in major histocompatibility complex (MHC) genes as determinants of adverse
200413
FACTORS INFLUENCING OUTCOMES FOLLOWING UNMANIPULATED HAPLOIDENTICAL TRANSPLANTATION
Reference
30 in patients who never developed GVHD. Patients with more CD56bright NK cells in the recovery stage had a higher survival rate.22,38,39 The reconstitution of killercell immunoglobulin-like receptors (KIR) after unmanipulated haploidentical transplantation recently has been reviewed in detail elsewhere. Reconstitution of B cells and monocytes is comparable between haploidentical transplant recipients versus HLA-matched recipients.17 Compared with MSD transplantation, the early reconstitution of myeloid dendritic cell 1 (MDC1), MDC2, and plasmacytoid dendritic cells was significantly delayed after haploidentical transplantation. Considering the early delayed immune reconstitution following unmanipulated haploidentical transplantation, strategies to improve immune recovery or posttransplantation vaccination should be investigated further.
Y.-J. Chang and X.-J. Huang
Table 2. Factors Associated With Clinical Outcomes Following Unmanipulated Haploidentical Stem Cell Transplantation
656
Haploidentical BMT without T-cell depletion
outcomes of HSCT may be less important when a RIC regimen containing anti–T-cell agents is used. Moreover, the low level of HLA gene heterogeneity observed in Korean patients may contribute to the favorable outcomes of HLA-haploidentical HSCT. However, these reasons cannot explain why HLA disparity does not appear to worsen OS after nonmyeloablative haploidentical BMT with high-dose post-transplantation Cy reported by the Baltimore group.10 Hence, further studies are necessary to elucidate the underlying mechanisms. The association of immune reconstitution with clinical outcomes, such as infection rates, TRM, or survival, has been confirmed both in HLA-matched sibling and unrelated donor transplant settings.46 In our transplant protocol, we found that early lymphocyte recovery correlates with superior survival.16 Chang et al39 also showed a survival advantage for patients with high early levels of CD56bright NK cells (day 14 CD56bright NK cells) after unmanipulated haploidentical transplantation. This result was recently confirmed by a Spanish group, using unmanipulated haploidentical bone marrow grafts after RIC.38 The association of alloreactive NK cells and transplantation outcomes of patients undergoing unmanipulated haploidentical transplantation has been recently reviewed in detail elsewhere.47,48 In summary, prospective studies with larger series of patients are needed to draw definitive conclusions on the impact of cell composition, HLA matching, and other factors in the T-cell–replete (TCR) nonmyeloablative or myeloablative haploidentical settings. These studies are necessary and important for predicting clinical outcomes such as infection rates, GVHD, and TRM and developing new methods for improving survival.
COMPARISON OF OUTCOMES BETWEEN UNMANIPULATED HAPLOIDENTICAL TRANSPLANT AND OTHER TRANSPLANT PROTOCOLS Several researchers have published retrospective studies highlighting the differences in unmanipulated haploidentical transplant versus HLA-matched sibling donor (MSD) transplantation, MUD transplantation, or unrelated double umbilical cord blood (dUCB) transplantation (Table 3). Lu et al49 found that leukemia-free survival and OS were comparable following unmanipluated haploidentical transplant and MSD transplantation, although unmanipulated haploidentical transplant was characterized by delayed early reconstitution of T cells and dendritic cells, as well as a higher incidence of CMV antigenemia. Several reasons may account for this finding: (1) compensatory expansion of monocytes and cytotoxic CD8⫹ lymphocytes17; (2) pre-emptive management of CMV antigenemia; (3) superior graft-versusleukemia effects associated with transplantation of haplo-identical compared with HLA-identical sibling do-
657
nor grafts for high-risk AL50; and (4) improvements in pharmacoprophylaxis of GVHD and supportive care. The same group also showed that for every major HSCT end point, including relapse, nonrelapse mortality, and survival, partially matched related and unrelated HSCT are not significantly different.51 The above-mentioned results also were demonstrated by Liu et al25 and Valcarcel et al,52 but in a multicenter study, Shaw et al53 showed that single HLA-mismatched related donor and MUD outcomes are similar, whereas HLA-MSD outcomes are superior. The Blood and Marrow Transplant Clinical Trials Network (BMTCTN) performed two independent, multicenter, phase II studies evaluating the outcomes of dUCBT and haploidentical BMT.54 Patients in these two treatment groups had similar eligibility criteria and used a similar nonmyeloablative conditioning regimen. One-year cumulative incidences of TRM and relapse were 24% and 31% after dUCBT and 7% and 45% after haploidentical transplantation, respectively. One-year OS and EFS were 54% and 46% after dUCBT and 62% and 48% after haploidentical transplantation, respectively. As two independent phase II studies,54 the results cannot be compared directly. Further investigation is required to directly compare the results of hematopoietic transplantation from different donor sources, including UCB, MSD, MUD, and haploidentical donors. Researchers from M.D. Anderson Cancer Center reported an interesting comparative study. Ciurea et al55 showed that patients who received TCR haploidentical transplants had better OS (66% v 30%, P ⫽ .02) and progression-free survival (45% v 21%, P ⫽ .03) at 1 year post-transplant compared with those who underwent TCD haploidentical transplantation. The investigators also found that improved transplant outcomes in the TCR group were related to significantly better immunologic reconstitution of T-cell subsets. They showed that CD4⫹ T cells recovered at day 180 following transplantation were significantly lower in the TCD group than those in the TCR group (64/L v 200.5/L, P ⫽ .04). These data warrant a randomized, prospective study to elucidate the superiority of unmanipulated transplantation compared to CD34-selected transplantation in the haploidentical setting.
STRATEGIES TO IMPROVE TRANSPLANT OUTCOMES AFTER UNMANIPULATED HAPLOIDENTICAL TRANSPLANT Currently, unmanipulated transplant represents a strategy in haploidentical settings that does not require the technical expertise and cost of ex vivo T-cell depletion. However, delayed platelet engraftment, high risk of relapse (after nonmyeloablative regimens) following transplantation, and early delayed immune reconstitution remain major limitations of unmanipulated
658
Table 3. Comparison of Unmanipulated Haploidentical Transplantation With HLA-Matched Related or Unrelated or Unrelated dUCB Transplantation Shaw et al, 201153 Multicenter Clinical Trial
No. of patients Age (yr) Sex, male/female, no. Dianosis AML ALL CML MDS Others Donor-recipient match 0 Mismatch 1 Mismatch 2 Mismatch 3 Mismatch Conditioning regimen
GVHD prophylaxis
MSD
mmRD
MUD
PMRD
MUD
1,208 9 (⬍1–17) 729/479
151 8 (⬍1–17) 96/55
266 9 (⬍1–17) 162/124
219 25 (5–53) 138/81
78 30 (10–49) 52/26
42 67 23 19 0
67 136 26 37 0
447 559 97 105 0
67 72 61 19 0
1,208 0 0 0 TBI-based regimen (47%) ATG-based regimen (99%) CSA/FK506⫾MTX (79%) CSA/FK506⫾others (21%)
0 151 0 0 TBI-based regimen (43%) ATG-based regimen (81%) CSA/FK506⫾MTX (85%) CSA/FK506⫾others (15%)
266 0 0 0 TBI-based regimen (20%) ATG-based regimen (81%) CSA/FK506⫾MTX (94%) CSA/FK506⫾others (6%)
0 27 87 105 Bu/Cy/ATG/MeCCNU ⫹Ara-C (4 g/m2/ d⫻2d) CSA/MTX/MMF
NA NA
NA NA
NA NA
7.2 (3.4–21) 2.2 (0.7–7.1)
NA
NA
NA
170 (10–830)
NA NA
NA NA
NA NA
13 (9–24) 15 (7–140)
29% (26–31) at d100 15% (13–17) at 1 yr 79 (2–171)
56% (48–64) at d100 30% (23–38) at 1 yr 62 (2–177)
45% (39–51) at d100 33% (27–39) at 1 yr 61 (12–168)
36% (33–39) at 3 yr
29% (22–37) at 3 yr
32% (27–38) at 3 yr
Brunstein et al, 201154 Multicenter Clinical Trial Unrelated dUCB 50 58 (16–69) NA
25 18 32 3 0
61 16 1 0 Bu/Cy/ATG/MeCCNU ⫹Ara-C (2 g/m2/ d⫻2d) CSA/MTX/MMF
Wang et al, 201150 Single-Center Clinical Trial
HID
MSD
HID
50 48 (7–70) NA
36 41 (15–56) 27/9
81 29 (5–50) 52/29
29 6 0 0 15
22 6 0 0 22
20 16 0 0 0
3 14 33 0 Flu/Cy/TBI (n ⫽ 50)
1 (8 of 10) 9 (7 of 10) 12 (6 of 10) 28 (5 of 10) Flu/Cy/TBI (n ⫽ 50)
MMF/CSA
MMF/CSA/ FK506/Cy
5.9 (1.7–15) 2.8 (0.8–10.6)
4.2 (3.1–16.3) NA
NA NA
6.8 (4.0–14) 2.5 (1.1–3.6)
7.1 (3.6–11) 2.9 (1.5–6.2)
220 (130–410)
NA
NA
190 (70–390)
180 (70–940)
16 (15–21) 15 (7–100)
13 (9–29) 15 (7–74)
12 (9–20) 13 (4–85)
15 (4–47) 43 (29–323)
16 (12–83) 24 (1–92)
47% (39–62) at d100 54% (47–61) at 2 yr 23 (0.3–60)
31% (20–42) at d100 40% (31–52) at 2 yr 22 (0.7–60)
12% (8–16) at 2 yr
18% (10–27) at 2 yr
40% (26–54) at d100 25% (12–39) at 1 yr 365 (56–411) days 31% (17–44) at 1 yr
32% (19–45) at d100 13% (3–23) at 1 yr 357 (103–441) days 45% (30–61) at 1 yr
36 0 0 0 Bu/Cy/ATG/MeCCNU ⫹Ara-C (4 g/m2/ d⫻2d) CSA/MMF/MTX
30 51 0 0 0
0 7 20 54 Bu/Cy/Hu/MeCCNU ⫹Ara-C (2 g/m2/ d⫻2d) CSA/MMF/MTX
24% (9–41) at d100 39% (20–58) at 2 yr 11 (0.6–46)
49% (37–61) at at d100 62% (49–75) at 2 yr 16 (0.8–59)
49% (31–67) at 2 yr
26% (15–37) at 2 yr
Y.-J. Chang and X.-J. Huang
Cell dose median TNC (⫻108/kg) CD34⫹ cells (⫻106/kg) CD3⫹ cells (⫻106/ kg) Engraftment (days) ANC engraftment PLT engraftment GVHD aGVHD IHV (% Cum. Incid.) cGVHD (% Cum. Incid.) Median follow-up (mo) Relapse (% Cum. Incid.)
Huang et al, 200951 Single-Center Clinical Trial
All values are given as median (% or range), unless otherwise specified. Abbreviations: HLA, human leukocyte antigen; dUCB, double umbilical cord blood; MSD, matched sibling donors; mmRD, mismatched related donors; MUD, matched unrelated donors; PMRD, partially matched related donors; HID, haploidentical donors; NA, not available; AML, acute myeloid leukemia; ALL, acute lymphoid leukemia; CML, chronic myeloid leukemia; MDS, myelodysplastic syndrome; Bu, busulfan; Cy, cyclophosphamide; ATG, anti-thymocyte globulin; TBI, total body irradiation; Ara-C, cytosine arabinoside; Me-CCNU, semustine; Hu, hydroxycarbamide; GVHD, graft-versus-host disease; CSA, cyclosporine A; FK506, tacrolimus; MTX, methotrexate; MMF, mycophenolate mofetil; TNC, total nuclear cells; ANC, absolute neutrophil count; PLT, platelet; TRM, transplant-related mortality; LFS, leukemia-free survival; OS, overall survival; Cum. Incid., cumulative incidence.
OS (% Cum. Incid.)
HID
34% (22–46) at 2 yr 42% (30–54) at 3 yr 42% (30–54) at 3 yr 38% (21–55) at 2 yr 15% (1–29) at 3 yr 20% (4–36) at 3 yr
MSD HID
7% (0–15) at 1 yr 48% (32–62) at 1 yr 62% (44–76) at 1 yr 24% (11–36) at 1 yr 46% (31–60) at 1 yr 54% (38–67) at 1 yr 18% (10–28) at 2 yr 61% (47–74) at 4 yr 74% (62–86) at 4 yr 20% (15–26) at 2 yr 67% (59–75) at 4 yr 74% (68–80) at 4 yr 24% (19–30) at 3 yr 43% (37–49) at 3 yr 32% (27–38) at 3 yr 2% (20–34) at 3 yr 44% (36–53) at 3 yr 29% (22–37) at 3 yr
Unrelated dUCB MUD PMRD MUD mmRD MSD
10% (8–12) at 3 yr 54% (51–57) at 3 yr 61% (58–64) at 3 yr TRM (% Cum. Incid.) LFS (% Cum. Incid.)
Table 3. Continued
Shaw et al, 201153 Multicenter Clinical Trial
Huang et al, 200951 Single-Center Clinical Trial
Brunstein et al, 201154 Multicenter Clinical Trial
Wang et al, 201150 Single-Center Clinical Trial
Haploidentical BMT without T-cell depletion
659
haploidentical HSCT. Thus, several strategies are being developed to improve clinical outcomes following haploidentical transplantation without ex vivo T-cell depletion.
Co-transplantation of Mesenchymal Stem Cells to Optimize Stem Cell Engraftment In adult patients undergoing transplantation from an HLA-identical sibling, mesenchymal stem cell (MSC) infusion was shown to be safe and possibly to accelerate hematopoietic recovery, as well as reduce the incidence of both acute and chronic GVHD.56 Ball et al2 cotransplanted donor-derived MSCs in 14 children undergoing TCD haploidentical transplantation. None of the patients given MSCs experienced either an adverse reaction or graft failure. The sustained donor engraftment observed in patients treated with MSCs compared favorably with the risk of rejection observed in haploidentical HSCT recipients, which has been reported in various studies to be 10%–20%.2 Recently, we conducted an open-label, randomized phase II clinical study to assess the outcome of MSC co-infusion (3– 5⫻105 cells/kg) during unmanipulated haploidentical HSCT.57 No immediate or long-term toxic side effects related to MSC infusion were observed. Within 100 days, the time to platelet concentration of ⬎50⫻109 cells/L was markedly faster in the treatment group compared with the control group (22 days v 28 days; P ⫽ .036). The cumulative occurrence of GVHD, relapse, leukemia-free survival, and OS were comparable between the treatment and control groups. The results reported by Ball et al2 and by our group57 suggest that co-transplantation of hematopoietic progenitors and MSCs may modulate host alloreactivity and/or promote better engraftment of donor hematopoiesis, reducing the risk of early graft failure when HLA disparity is present in the donor/recipient pair. The mechanisms may be related to higher concentrations of stromal cell– derived factor-1␣ (SDF-1␣), thrombopoietin, and interleukin-11.57
G-CSF–Primed DLI to Decrease Relapse In previous studies, we administered G-CSF–primed DLI prophylactically to 29 patients and therapeutically to 20 patients. Two-year EFS was 37.3% for recipients of prophylactic DLI and 40% after therapeutic DLI.58,59 These preliminary data suggest that G-CSF–primed DLI is safe and effective for both prophylaxis against relapse and treatment of recurrence after unmanipulated haploidentical transplantation. In a retrospective study,60 we analyzed the data of 88 patients with advanced-stage AL after unmanipulated haploidentical HSCT whose treatment did (n ⫽ 61) or did not (n ⫽ 27) include G-CSF–primed DLI. The 2-year cumulative incidences of relapse in patients receiving prophylactic DLI versus not receiving prophylactic DLI were 36%
660 and 55% (P ⫽ .017), respectively. Estimated OS and EFS at 3 years were 31% and 22%, respectively, for patients receiving prophylactic DLI, and 11% and 11%, respectively, for patients not receiving prophylactic DLI (P ⫽ .001 and .003, respectively). Multivariate analysis showed that use of prophylactic DLI after transplantation was an independent prognostic factor for relapse. Higher OS was associated with use of prophylactic DLI, acute myeloid leukemia, and female sex.60 Our results further suggest that use of prophylactic DLI may increase survival of patients with advanced-stage AL who receive HLA-mismatched/haploidentical HSCT. For acute lymphocytic leukemia patients receiving allografts from haploidentical donors, other methods should be investigated to decrease relapse and improve transplant outcomes. Further study to investigate the dose-response relationships for both GVHD and antitumor efficacy are clearly required before DLI can be routinely recommended for the prevention or treatment of relapse after unmanipulated haploidentical HSCT.
Methods to Enhance Immune Reconstitution After Unmanipulated Haploidentical Transplantation Regulatory T cells (Tregs) play a key role in the prevention and treatment of acute GVHD after allogeneic BMT in murine models.61 In recent clinical trials, the infusion of Tregs after haploidentical62 and UCB63 stem cell transplantation to prevent GVHD and promote immune reconstitution has produced promising results. The Peking University group41 found that that a large population of CD62L⫹ naive Tregs (CD4⫹CD25highCD45RA⫹CD62L⫹ T cells) in allografts reduces the incidence of acute GVHD. Further, development of acute GVHD is related closely to the delayed reconstitution of the naive Treg population. Taken together, these data suggest that a clinical trial should be designed to evaluate the effects of Tregs on acute GVHD prevention and immune recovery promotion in haploidentical HSCT settings without ex vivo T-cell depletion. In unmanipulated haploidentical transplant settings, we found early delayed immune reconstitution, although CD4⫹ cells recovered to nearly 200/L at day 180 after transplantation.17,55 Therefore, recombinant interleukin-2 was administered as a consolidating immunotherapeutic agent early after HSCT at a time of minimal residual disease, which may reduce the relapse rate and increase the immunocompetence of these patients.64 This could be because of a lymphoid orientation of primitive CD34⫹CD105⫹ cells, which express high-affinity interleukin-2 receptors. Exogenous interleukin-2 might thus lead to an enhancement of the graft-versus-leukemia (GVL) effect.64,65 Our findings also support that measuring levels of CTLCMV and its
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subsets in the donor grafts and manipulating these cells early after transplantation may help control CMV reactivation, which correlates closely with immune reconstitution and differentiation of CTLCMV subsets.66 To improve clinical outcomes, novel strategies to enhance immune reconstitution after unmanipulated haploidentical HSCT should be explored in the future.67,68
FUTURE DIRECTIONS Over the past several years, unmanipulated haploidentical transplantation has been adopted by more and more transplant centers worldwide.6,7,9,10,33–38,69 –72 The advantages of haploidentical donors without TCD as a stem cell source are: (1) absence of the technical expertise and cost of ex vivo T-cell depletion6,8; (2) high T-cell content of allografts potentially enhances the GVL effect50; and (3) accelerated immune reconstitution compared with CD34-selected haplotype-mismatched transplants.37 The disadvantages of unmanipulated haploidentical transplant include: (1) potentially severe GVHD induced by T cells6,8; and (2) a high incidence of leukemia relapse for patients receiving reduced-intensity protocols.31 Considering the advantages and disadvantages of haploidentical donor without TCD and the fact that different conditioning regimens, different GVHD prophylaxis, and different stem cell grafts were used by different transplant groups,10,12–14,23,31,49,54 the kinetics of immune reconstitution, and factors associated with clinical outcomes should be investigated at different transplant centers to improve survival. Currently, TCR and TCD HSCT represent two main transplant protocols in haploidentical transplant settings.6,8 However, we cannot promote a definitive strategy for haploidentical transplant protocol selection because each has its own advantages and disadvantages. Therefore, prospective randomized comparative studies and clinical trial participation is encouraged. In addition, future randomized studies will be required to compare UCB, haploidentical donor, and mismatched unrelated donor to more conventional related and MUD sources. It is reasonable that the above-mentioned studies will allow us to make individual therapeutic choices for patients in the future.
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