Haploidentical Stem Cell Transplantation for Acute Myeloid Leukemia: Current Therapies, Challenges and Future Prospective

Haploidentical stem cell transplantation (haplo-SCT), an alternative donor source, offers a curative therapy for patients with acute myeloid leukemia (AML) who are transplant candidates. Advances in transplantation techniques, such as donor selection, conditioning regimen modification, and graft-versus-host disease prophylaxis, have successfully improved the outcomes of AML patients receiving haplo-SCT and extended the haploidentical transplant indictions for AML. Presently, treating de novo AML, secondary AML, therapy-related AML and refractory and relapsed AML with haplo-SCT can achieve comparable outcomes to those of human leukocyte antigen (HLA)-matched sibling donor transplantation (MSDT), unrelated donor transplantation or umbilical cord blood transplantation. For some subgroups of AML subjects, such as patients with positive pretransplantation minimal/measurable residual disease, recent studies suggest that haplo-SCT might be superior to MSDT in decreasing relapse and improving survival. Unfortunately, for patients with AML after haplo-SCT, relapse and infections remain the causes of death that restrict further improvement in clinical outcomes. In this review, we discuss the recent advances and challenges in haplo-SCT for AML treatment, mainly focusing on unmanipulated haplo-SCT protocols. We provide an outlook on future prospects and suggest that relapse prophylaxis, intervention, and treatment, as well as infection prevention and therapy, are areas of active research in AML patients who receive haploidentical allografts.

In the past two decades, advances in the establishment of algorithms for best haploidentical donor selection (40)(41)(42), optimization of conditioning regimens (43)(44)(45), shifts from TCD grafts to unmanipulated bone marrow and/or peripheral blood harvests (3,5,21,46,47), enhancement of hematopoietic recovery through endothelial cell-directed N-acetyl-L-cysteine intervention and/or donor-specific antibody desensization (34,48,49), biomarker-directed graft-versus-host disease (GVHD) prophylaxis (50)(51)(52), minimal/measurable residual disease (MRD)-directed relapse intervention (7,53), and approaches for enhancing immunologic recovery (54)(55)(56) have successfully improved the outcomes of patients with hematological malignancies, especially those with AML receiving haplo-SCT. Unfortunately, for subjects with AML who underwent haploidentical allografts, relapse and infections remain the causes of death that restrict further improvement in clinical outcomes (57,58). In this review, we discussed the current therapies and challenges in haplo-SCT for AML treatment, mainly focusing on unmanipulated haploidentical transplant protocols. We provide an outlook on future prospects and suggest that relapse prophylaxis, intervention, and treatment, as well as infection prevention and therapy, are areas of active research in AML patients who receive haploidentical allografts.
The extension of indications promotes the use of haploidentical allografts in patients with AML worldwide (76,77). According to the data of the Chinese Blood and Marrow Transplantation Register Group (CBMTRG) (76), haploidentical donors have been the first donor source for AML since 2013. The number of AML patients who received haplo-SCT reached nearly 2000 in 2015. In a recent survey by the European Society for Blood and Marrow Transplantation (EBMT) (77), the number of haplo-SCTs in Europe 2019 (n=1813) was listed as the third transplant modality for AML. In 2019, the number of haplo-SCTs was more than two thousand and comparable to that of MSDT according to the report of the Center for International and Marrow Transplant Research (CIBMTR), although fewer than 700 AML patients received haplo-SCT (78).

OUTCOME COMPARISON BETWEEN HAPLO-SCT AND OTHER TRANSPLANT MODALITIES
In 2006, our group demonstrated for the first time that treating leukemia patients with haplo-SCT achieved comparable 2-year nonrelapse mortality (NRM), cumulative incidence of relapse (CIR), and 2-year probabilities of leukemia-free survival (LFS) and overall survival (OS) to those of MSDT (31), suggesting that haplo-SCT is a feasible approach with acceptable outcomes. Since then, a series of retrospective or prospective studies reported by others (4, 10, 26, 64-70, 74, 75, 79-87) and us (6,(88)(89)(90) compared the outcomes of AML patients who either received haplo-SCT or other allografts, including MSDT, HLAmatched unrelated donor transplantation (MUDT) and Tregs, regulatory T cells; Tcon, conventional T cells; MSDT, human leukocyte antigen (HLA)-matched sibling donor transplantation; G-CSF, granulocyte colonystimulating factor; ATG, anti-thymocyte globulin; PTCy, posttransplantation cyclophosphamide; TBI, Total body irradiation; SS-BM, steady-state bone marrow; G-PB, G-CSF mobilized peripheral stem cells; GVHD, graft-versus-host disease; MMF, mycophenolate mofetil; G-BM, G-CSF-stimulated bone marrow harvests; MTX, Methotrexate; Bu, Busulfan; CSA, Cyclosporin A *Subcutaneous injection starting on Day 4 and continuing until recovery of neutrophils to >1000/ml for 3 days. # Tacrolimus was initiated at a dose of 1 mg i.v. daily, adjusted to achieve a therapeutic level of 5-15 ng/mL, and then converted to oral form until discontinuation. If there was no active GVHD, tacrolimus was tapered off by Day 180. **Sirolimus (orally, monitored 2 times each week to maintain a target therapeutic plasma level of 8 to 14 ng/mL during the first 2 months after transplantation, thereafter of 5 to 8 ng/mL until discontinuation). ## Patients 50 years old or older were conditioned with the same regimen as in (D), except for lower dosages of Bu (6-8 mg/kg) and Cy (1.0 g/m 2 /d).    umbilical cord blood transplantation (UCBT). Here, we mainly focused on published studies that compared the outcomes between HIDs and other donors in the last five years ( Table 1).

Clinical Outcomes Between Haplo-SCT and MSDT
In 2015, researchers from China reported the results of a multicenter, prospective study that compared the outcomes of AML patients in CR1 who either underwent haplo-SCT (n=231) or MSDT (n=219) (6). Wang et al. (6) (6,79), other scholars also confirmed the similarity between haplo-SCT and MSDT in treating AML in CR2, secondary AML, poor-risk AML and refractory/relapsed AML ( Table 1) (64,70,80). More recently, in a prospective multicenter cohort study, Yu et al. (92) showed that treating high-risk AML in CR1 with haploidentical allografts could significantly decrease the cumulative incidence of positive posttransplant MRD (18% vs. 42%, P<0.001) and increase the probability of 3-year GVHD and relapse-free survival (63% vs. 43%, P=0.035) compared with those who received allografts from MSDs. These results suggest that haplo-SCT has a stronger graftversus-leukemia (GVL) effect than MSDT in high-risk AML patients in CR1 (92). Thus, increasing evidence supports the notion that haplo-SCT should be recommended as one of the optimal postremission therapy choices for transplant candidates with AML.
In a recent meta-analysis, Yang et al. (93) demonstrated that haplo-SCT, either the Baltimore protocol or the Beijing protocol, could achieve comparable 1-year CIR (OR, 0.83; P=0.180) and NRM (OR, 0.98; P=0.910) to those of MSDT in another metaanalysis, which included 24 studies and 11,359 cases. Overall, the literature published thus far (64,70,80) suggests that for patients with AML, MSDs remain the first choice when HIDs are also available due to the early delayed immune recovery and higher infection rate following haplo-SCT compared to those with MSDT (58,94).
For poor-risk AML in CR1, Versluis et al. (70) observed that haplo-SCT could achieve comparable outcomes to those of 10/10 matched MUDT but superior outcomes to those of 9/10 matched MUDT. Patients with refractory/relapsed AML who underwent haploidentical allografts experienced comparable outcomes to those of patients who received either MUDT or mismatched unrelated donor transplantation (MMUDT) (85). Ongoing prospective, randomized studies are performed to validate the disadvantages and advantages between haploidentical allografts and MUDT (NCT04067180 and NCT04232241), although current data (4,24,70,83,85,86,95) suggest that an HID is a valid option for high-risk AML patients in CR1 or with active disease as well as R/R AML.
Based on the results of the meta-analysis, Arcuri et al. (96) observed that treating hematological malignancies with PTCybased haplo-SCT could achieve a similar OS rate (HR, 0.98) to MUDT. However, the incidence of all forms of GVHD (2-4 aGVHD, HR, 0.52; cGVHD, HR, 0.25) and NRM (HR, 0.85) was lower after haplo-SCT than after MUDT. Gagelmann et al. (97) showed that, compared with MMUDT, haplo-SCT with PTCy was associated with reduced all-cause mortality (OR, 0.75) and better outcomes (OR, 0.51). Overall, HIDs could be an alternative stem cell source for treating subjects with AML, especially poor-risk subjects, who lack MSDs in experienced centers due to easy access to first and second stem cell harvests, although the current algorithm suggests that MUDs (10/10) should be preferred to HIDs (42,98).

Clinical Outcomes Between Haplo-SCT and UCBT
In 2011, a 2 parallel multicenter phase 2 trial performed by Brunstein et al. (99) provided preliminary results indicating that the outcomes between double UCBT and haplomarrow transplantation with reduced intensity conditioning (RIC) regimens in treating leukemia and lymphoma are comparable to those reported after MUDT. However, from the point of view of graft acquisition and early direct charges, haplo-SCT may result in early cost savings over double UCBT and may be preferred by transplant centers and patients with more limited resources, as described by Kanate et al. (100) In 2019, Ruggeri et al. (84) retrospectively analyzed the outcomes of 409 adults with secondary AML receiving either UCBT (n=163) or haplo-SCT (n=246) in EBMT centers. They observed a higher risk of grade II-IV acute GVHD (HR 1.9, P=0.009) and lower GHVD-free relapse-free survival (GRFS) (HR 1.57, P=0.007) after UCBT for subjects with AML compared to haploidentical allografts. These results indicate that haplo-SCT is associated with better GRFS and lower acute GVHD than UCBT in patients with secondary AML. For poor-risk AML patients, Versluis et al. (70) found that compared with UCBT, haplo-SCT was associated with higher RFS (52% vs. 41%, P<0.001).
More recently, in 2 parallel phase II trials, 368 patients aged 18 to 70 years with chemotherapy-sensitive lymphoma or acute leukemia in CR were randomly assigned to the UCBT group (n=186) or haplo-SCT group (n=182) (65). Prespecified analysis of secondary end points demonstrated lower 2-year NRM after haplo-SCT than that of UCBT (11% vs. 18%, P=0.04), which led to higher OS after haplo-SCT compared with that of UCBT (57% vs. 46%, P=0.04), but the PFS was comparable (35% vs. 41%, P=0.41). Fuchs et al. (65) suggested that although both donor sources extend access to RIC transplantation, analyses of secondary end points, including OS, favor HIDs.
Overall, the landscape of allografts for hematological malignancies apparently changed with the position alteration of haplo-SCT in AML treatment (5,11,13,22,(59)(60)(61). Most scholars agree that for patients with hematological malignancies, including AML, who lack MSDs and urgent transplantation, HIDs could be selected first. Impressively, based on the dataset of the Acute Leukemia Working Party of the EBMT registry, Dholaria et al. demonstrated that 9/10 MUDT with PTCy may be preferred over UCBT if a 10/10 matched unrelated donor is not available (72) (Figure 2A). Currently, a few retrospective studies compared the clinical outcomes between the Beijing Protocol and the Baltimore protocol in treating patients with hematological malignancies (73,101,102), however, the results among different studies remain controversial. Therefore, prospective, multicenter, randomized studies are needed.

CHALLENGES OF HAPLOIDENTICAL ALLOGRAFT IN AML TREATMENT
According to the CIBMTR data, relapse remains an important challenge in AML patients who undergo haploidentical allografts. Infection is another challenge following haplo-SCTbased immune tolerance induced either by G-CSF and ATG or by PTCy (57,58,103,104). Here, we discussed the recent emerging strategies for relapse or infection intervention or treatment for AML subjects.

Could HIDs Be Selected First for Subgroup AML Patients to Decrease the Relapse Rate?
According to the current opinion, MSDs remain the first choice for transplant candidates with AML, although comparable outcomes were observed between haplo-SCT and MSDT (42,105). However, we found that for all AML patients with positive pretransplantation MRD, haplo-SCT patients experienced a lower CIR and better LFS and OS than MDST patients (25,(106)(107)(108)(109). These results suggest a stronger GVL effect of HIDs than MSDs. We further confirmed the stronger GVL effects after haplo-SCT than MSDT in AML subgroups with positive pretransplant MRD, including t(8;21) AML (25), Flt3 mutation-positive AML (110), and high-risk AML patients in CR1 (92) ( Table 3). Interestingly, the stronger GVL effect of HIDs compared with MSDs was also confirmed in ALL patients with positive pre-MRD (111) and lymphoma subjects (105). More recently, a study from the Acute Leukemia Working Party of the EBMT showed that ALL patients treated with haplo-SCT experienced a significantly lower 2-year CIR than those of patients receiving MSDT (HR=0.63, P=0.002) (112), which provides new evidence supporting the stronger GVL effect of HIDs.
More recently, haploidentical and major histocompatibility (MHC)-matched transplant models were established by Guo et al. (25) after infusion of leukemia cells that carried the human AML-ETO or MLL-AF9 fusion gene to investigate the immune cell dynamic response during leukemia development in vivo. They showed that haplomatching the MHCs of leukemia cells with recipient mouse T cells prolonged leukemic mouse survival and reduced leukemia burden (25). The stronger GVL activity in the haplo-SCT group was mainly induced by decreased apoptosis and increased cytotoxic cytokine secretion, including tumor necrosis factor-a, interferon-g, pore-forming proteins and CD107a secreted by T cells or natural killer (NK) cells (25).
Overall, in contrast to the traditional notion that MSDs remain the first choice, recent advances in haploidentical transplantation settings raise a new idea (92,105,107,108,(110)(111)(112)(113)(114): for some subgroups of AML patients, HIDs might be chosen first (19), although further research is needed before this could be included in the donor selection algorithm (115,116).

Could the Best HIDs Be Selected to Decrease CIR of AML?
Donor characteristics are important variables for transplant outcome determination. In haplo-SCT settings, we and other researchers suggest a donor selection algorithm for which the key issue is that the younger the better (42,117,118). Regarding the best donor selection in AML patients treated with haplo-SCT, NK cell alloreactivity (KIR ligand mismatch between recipients and donors) was associated with better survival in AML patients who received haplo-SCT with ex vivo TCD. However, in unmanipulated haplo-SCT settings, KIR ligand mismatch was not associated with better survival of acute leukemia patients (42,119,120). Our group found that, compared to subjects with KIR ligand mismatch, cases with KIR ligand match were associated with rapid quantitative and functional NK cell recovery, which could contribute to lower CIR and better survival of AML cases treated with the Beijing Protocol (121). In a recent multicenter retrospective study, 1270 patients with acute lymphoma, including AML (n=1019) and ALL (n=251), received haplo-SCT using a myeloid ablative conditioning regimen or RIC. Cannani et al. (40) showed that for cases with age >40, donor age (>40) was correlated with higher NRM and inferior LFS and OS. Unfortunately, the current algorithm for the best HID selection is mainly based on the results obtained from the total patient population (41,122). Therefore, multicenter, prospective studies are needed to answer the question of who is the best HID for AML patients, especially in unmanipulated haplo-SCT settings.

Could We Incorporate Novel Methods With
Haplo-SCT for R/R AML Treatment? Venetoclax (VEN), a BCL-2 inhibitor, has been approved for unfit, older patients with AML (123,124). In a recent study, sixty-eight patients, including newly diagnosed AML (ND AML) and R/R AML, were enrolled [phase IB (PIB), 16  months; P=0.009). This study provides a promising approach, combining FLAG-IDA+VEN with allografts, for the treatment of R/R AML.
To treat a patient with FUS-ERG + AML who relapsed after allo-SCT within 3 months and resisted multiagent chemotherapy and donor lymphocyte infusion (DLI), Yao et al. (126) used donorderived CD123-targeted CAR T cells (CART123) as part of a conditioning regimen for haplo-SCT. They observed a reduced blast level in BM within 2 weeks, which coincided with CAR copy expansion. After achieving full donor chimerism, this patient achieved CR with incomplete blood count recovery. These results suggest that CART123 in combination with haplo-SCT could be used as a therapy for relapsed AML subjects.

Could We Incorporate Other Approaches for AML Relapse Treatment and Prevention After haplo-SCT?
The outcomes of AML patients who relapse after allografts remain poor, with a 5-year OS of less than 20%, and either DLI or second allo-SCT is prescribed (138). More recently, Cui et al. (139) enrolled 6 AML patients who relapsed after transplantation. The median percentage of CD38 expression on blasts in the bone marrow of these patients was 95% before CD38-targeted CAR-T cell (CAR-T-38, 4 from autologous and 2 from donors) treatment. Four of six (66.7%) patients achieved CR or CR with incomplete count recovery (CRi) 4 weeks after the initial CAR-T-38 cell therapy. The CIR at 6 months was 50%. The median times of OS and LFS of these cases were 7.9 and 6.4 months, respectively. One patient who relapsed 117 days after the first CAR-T-38 treatment achieved remission after the second CAR-T-38 cell infusion. The side effects of these patients were manageable. There were no off-target effects on monocytes and lymphocytes. Although a limited number of cases and a relatively short follow-up time were presented by Cui et al. (139), their preliminary data highlight the clinical utility and safety of CAR-T-38 cell therapy in treating relapsed AML following allo-SCT. Several trials (NCT02782546, 04024761, 03300492) investigating the feasibility of immunotherapy with NK cells are ongoing ( Table 4).
Considering the poor outcomes of HR-AML, a number of strategies for relapse prophylaxis or prevention have been used in the clinic (140). In a phase II, open-label, multicenter, randomized controlled trial (141), 204 HR-AML subjects with negative MRD who had received allo-SCT (mainly haplo-SCT, n=148) 60-100 days before were randomly (1:1) assigned to either no intervention (non-G-Dec group) or rhG-CSF combined with minimal dose Dec (G-Dec group: 100 mg/m 2 of rhG-CSF on Days 0-5 and 5 mg/m 2 of Dec on Days 1-5). Gao et al. (141) observed that patients in the G-Dec group experienced a lower 2-year CIR (15.0% vs. 38.3%, P=0.01) accompanied by rapid recovery of CD8 + T cells, NK cells, and regulatory T cells compared with patients in the non-G-Dec group, both of which led to higher LFS (HR=0.38, P<0.01) and OS (HR=0.45, P=0.01). No differences in the 2-year chronic GVHD without relapse between the two groups (23.0% vs. 21.7%, P=0.81) were shown. The authors (141). suggest that rhG-CSF combined with minimal-dose Dec maintenance therapy following transplantation can reduce the CIR, leading to the acquisition of GVL effects and immune tolerance.
Impressively, data from two independent randomized trials (15,142) show that sorafenib maintenance posttransplantation, including haplo-SCT, prevents disease relapse in patients with FLT3-ITD AML both with negative or positive MRD after allograft transplantation, resulting in an OS benefit. A previous study by Mathew et al. (143), in allograft settings, showed that sorafenib increased IL-15 production by FLT3-ITD + leukemia cells. IL-15 further caused an increase in CD8 + CD107a + IFN-g + T cells with high levels of Bcl-2 and reduced PD-1 levels, and this cell subset could eradicate leukemia in secondary recipients. These studies (15,142) provided strong evidence indicating that targeted posttransplant maintenance therapy should be a new treatment paradigm for AML, although questions remain. Moreover, additional studies are needed to investigate the optimal initial time and duration of sorafenib maintenance after allo-SCT as well as to elucidate the underlying mechanisms of sorafenib activity in the allograft setting.
In summary, the successful application of new strategies following allografting (15,137,142,144), such as rhG-CSF combined with minimal-dose Dec, Aza plus VEN (NCT04809181), and targeted agent maintenance, could help AML patients avoid hematological relapse as much as possible, thus decreasing the CIR and improving the survival rate ( Figure 2B).

Could Infections Be Effectively Prevented Using Adoptive Cell Therapy?
In haplo-SCT with the G-CSF modality, the cumulative incidence of cytomegalovirus (CMV) DNAemia varies from 63.7 to 66.1% and remains one of the main causes of morbidity and mortality. BKV and EBV infection are also frequent in haplo-SCT and a risk factor for worse survival except for CMV infection (58,145). For cases with refractory CMV infection who failed to respond to ganciclovir, foscarnet, and cidofovir, adoptive T-cell therapies, such as CMV-specific Tcells (CMV CTLs), represent a promising approach (146,147). Using a humanized HCMV-infected mouse model, our group further elucidated that systemic HCMV infection could be combated after first-line therapy with CMV CTLs via in vivo promotion of the recovery of graft-derived endogenous CMV CTLs (55). These studies provide substantial evidence suggesting that refractory CMV infection could be successfully treated by adoptive transfer of CMV CTLs. Future studies should focus on risk factor-directed intervention or the development of new drugs for CMV infections in haplo-SCT settings.
Olson et al. (148) performed a clinical trial in which HLAmatched third-party BKV-specific CTLs were infused into 59 patients who developed BKV-HC following allo-SCT. They observed a rapid response to BKV-CTL infusion. The Day 14 and Day 45 overall response rates were 67.7% and 81.6%, respectively. No patient lost a previously achieved response. There were no cases of de novo grade III or IV GVHD, graft failure, or infusion-related toxicities. BKV-CTLs were observed in patient blood samples up to 3 months postinfusion, and their in vivo expansion predicted a clinical response. This study suggests that off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after allo-SCT (148). Therefore, rapid reconstitution of immunity to a broad range of viral and fungal infections can be achieved using a multipathogen-specific T-cell product (147,149).
In summary, recent studies (147) showed some promising preliminary data and ongoing clinical trials on AML relapse prophylaxis, intervention, and treatment ( Figure 2B and Table 4), as well as infection prevention and therapy. Both of these factors will pave the way for outcome improvements for patients with AML who undergo haploidentical allografts.

FUTURE PROSPECTS
In the next five to ten years, the issue of relapse and infections remains to be solved, although haplo-SCT has been rapidly expanded in AML treatment (5,11,13,22,(59)(60)(61). Regarding relapse, elucidating the mechanisms underlying leukemia recurrence remains the most important way to find novel targets for intervention or treatment of relapse. Recently, the application of single-cell sequencing techniques has been used for the following purposes (150)(151)(152)(153)(154)(155)(156)(157)(158)(159)(160): i) identifying differentiated AML cells with immunosuppressive properties; ii) dissecting the clonal heterogeneity of AML; iii) providing novel insights into  the clonal evolution and resistance mechanisms of leukemia cells; iv) identifying novel targets for AML therapy; and v) highlighting the profound impact of AML on NK cell heterogeneity. These advances provide new clues and suggest that we could further discover new mechanisms underlying leukemia relapse after transplantation based on the abovementioned new techniques as well as in vitro and in vivo functional experiments. In addition, based on current available data (25,106,108,113,140,161), at different timepoints (pre-and posttransplantation), realization of individual therapy of AML by combining haplo-SCT with other novel methods (113), such as CAR-T therapy, target agents, and others, should be investigated. Could changing positive MRD to negative MRD pretransplantation further improve clinical outcomes? Which is the best method for positive pretransplant MRD eradication? For patients with intermediate-or adversestratification, should maintenance after transplant be given routinely? To answer these questions, prospective, multicenter, randomized clinical trials are urgently needed.
Infections, especially viral infections, are of concern. Both in the Beijing Protocol and the Baltimore Protocol, the delayed reconstitution of CMV-specific CTLs and NK cells was associated with CMV reactivation (58,145). Therefore, enhancing CMV-specific CTL and NK cell recovery represents a future direction for virus infection prevention, including CMV, EBV, and BKV. Unfortunately, overcoming the functional impairments of adaptive NK cells to produce IFN-g (162), a phenomenon due to the virus-induced expression of lymphocyte activation gene 3 and programmed cell death protein 1 checkpoint inhibitors, remains to be investigated. In addition, a phase II multicenter, randomized trial is ongoing to investigate the protective function of the CMV-MVA triplex vaccine in adult recipients who received haplo-SCT (NCT 04161885).

CONCLUSION
Recent advances in haploidentical allografts have significantly changed their position in AML treatment (5,11,13,22,(59)(60)(61). Their combination with novel therapies, such as CAR-T cells and Ven, could make more R/R patients with AML eligible for curative haplo-SCT who previously experienced poor outcomes when receiving allografts in relapse or NR status (125). Ongoing studies focusing on relapse, infections, and hematopoietic and immunological reconstitution enhancement would further improve haploidentical transplant outcomes of AML. In the long term, biomarkers (163,164), such as MRD, directed donor selection (108), conditioning selection (14), and immunological enhancement for relapse intervention (165), will help us realize precision medicine in the setting of haplo-SCT for treating patients with AML.

AUTHOR CONTRIBUTIONS
Y-JC and X-JH designed the study. All authors contributed to data interpretation, manuscript preparation, and approval of the final version.