Clinical Hematology International Vol. 1(3), September 2019, pp. 154–160 DOI: https://doi.org/10.2991/chi.d.190613.001; eISSN: 2590-0048 https://www.atlantis-press.com/journals/chi/ Review Allogeneic Stem Cell Transplantation with CD34+ Cell Selection Elisa Roldan1 , Miguel Angel Perales2,* , Pere Barba1,* 1 Hematology Department, Vall d’Hebron University Hospital-Universitat Autónoma de Barcelona, Pg. Vall Hebron 119, Barcelona, Spain 2 Adult BMT Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA ARTICLE INFO ABSTRACT Article History The success of allogeneic stem cell transplant is hampered by the development of acute and chronic graft-versus-host disease Received 19 March 2019 (GvHD) which has direct impact on treatment-related mortality and morbidity. As a result, T cell depletion through positive Accepted 04 June 2019 selection of CD34+ cells has emerged as a promising strategy to reduce acute and chronic GvHD in these patients. In this review, we summarize the main characteristics of allogeneic stem cell transplant with CD34+ cell selection including risks Keywords of graft failure, GvHD, infection, organ toxicity, and long-term survival. Moreover, we highlight future strategies to improve the Allogeneic transplant results of this platform and to consolidate its use in clinical practice. Graft-versus-host disease T cell depletion CD34+ cell selection Graft-versus-host disease-free and relapse-free survival (GRFS) © 2019 International Academy for Clinical Hematology. Publishing services by Atlantis Press International B.V. This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/). 1. INTRODUCTION Table 1 CD34+ cell selection as compared to unmodified alloSCT. Graft rejection No higher incidence if myeloablative conditioning Allogeneic stem cell transplant (alloSCT) is a curative therapy for and ATG a large number of malignant and nonmalignant hematological dis- GvHD Decreased incidence of acute and chronic GvHD eases. However, graft-versus-host disease (GvHD) is one of the Toxicity Decreased renal toxicity Better tolerance in older age and in patients with main causes of treatment-related mortality (TRM) and morbidity, comorbidities and may impair posttransplant quality of life [1]. The risk of grade Immune Delay in immune recovery of CD4+ cells II–IV acute GvHD is around 30%–50% in recipients of Human reconstitution Inversion of CD4+/CD8+ ratio Infections Increased incidence of opportunistic infections, Leukocyte Antigen (HLA) identical siblings, while it varies between especially viral 40% and 70% in unrelated donor transplants [2]. Recently, multiple Relapse Similar results in AML, MDS, ALL strategies have been used to optimize the management of GvHD, Disease free survival Similar results in AML, MDS, ALL Overall survival Similar results in AML, MDS, ALL both in the prophylactic and treatment settings. Among them, the Quality of life Fewer hospital admissions role of ex vivo T cell depletion (TCD) with positive selection of No inmunosupression post-SCT CD34+ cells in the graft has been investigated, based on the impor- Abbreviations: GvHD: Graft-versus-host disease; AML: acute myeloid leukemia; tance of alloreactive T cells for the development of GvHD [3–5]. In MDS: myelodysplastic syndrome; ALL: acute lymphoblastic leukemia; SCT: Stem cell this review, we summarize the characteristics of this transplant plat- transplantation. form (Table 1) including recent data that will contribute to optimize used, the subtypes of depleted cells, the source of stem cells, and the this modality of alloSCT. use and type of posttransplant immunosuppression. Every selection technique generates a specific graft in terms of quality and quantity of depleted cells [6–8]. 2. METHOLOGY The ex vivo TCD of the graft can be carried out either by positive In the last decades, different TCD methodologies have been pro- or negative selection [9]. The most frequently used techniques to posed, including ex vivo depletion techniques. The effectiveness of achieve the TCD of the product are based on the positive selection the latter in preventing GvHD varies with the technical procedure of CD34+ cells through electromagnetic methods such as ISOLEX 300i (Baxter, Deerfield, IL) (nowadays disused) and, especially, the * CliniMACS CD34 Reagent System (Miltenyi Biotec, Bergisch Glad- Corresponding authors. Ph.: +34.93.274.64.14. E-mail: pbarba@vhio.net (PB); Ph.: 212-639-8682; Fax: 212-717-3500. E-mail: peralesm@mskcc.org (MAP) bach, Germany), which allow an up to 5-log reduction of T cells in Pdf_Folio:154 Peer review under responsibility of the International Academy for Clinical Hematology the final product [8,10,11]. E. Roldan et al. / Clinical Hematology International 1(3) 154–160 155 More recently, other TCD strategies have been developed including added additional observations: 1) Acute GvHD in this type of trans- 𝛼𝛽+ TCR/CD19 depletion. This methodology may produce a bet- plants is mostly cutaneous and upper gastro-intestinal. 2) Acute ter immune response against viral infections, with low risk of acute GvHD can be managed in the majority of patients with topical or GvHD [12] by enhancing 𝛾𝛿 T cell reconstitution and lowering 𝛼𝛽+ limited oral absorption corticosteroids. Therefore, only a minority TCR counts after transplantation. Noteworthy, most of the data on of patients with GvHD required systemic immunosuppressive treat- 𝛼𝛽+ TCR/CD19 depletion come from pediatric studies using hap- ment. 3) Reduction of GvHD is especially relevant in its chronic loidentical donors [13,14] and need further investigation in the set- form (incidences <10% in successive studies [22]). This decrease ting of matched-related or unrelated donor transplants in adults. in chronic GvHD could have an impact on posttransplant qual- ity of life and on other variables such as length of hospitalization and use of nutritional support [4,30]. Unfortunately, at the present 3. CLINICAL IMPLICATIONS OF CD34 time, there are no comprehensive studies of quality of life focused POSITIVE SELECTION on CD34+ selection alloSCT. A prospective multicenter randomized phase III study (BMT CTN 3.1. Engraftment 1301, NCT02345850) is currently ongoing in AML and MDS Initially, CD34+ cell selection showed a moderately increased risk of patients who are randomized to receive one of three different strate- graft failure compared with other transplant modalities [15]. How- gies to prevent GvHD: CD34+ cell selection (using peripheral blood ever, successive modifications in the initial platform, including the as stem cell source), posttransplant cyclophosphamide (using bone use of peripheral blood progenitors (as opposed to the initial use marrow) and a conventional GvHD prophylaxis with tacrolimus of bone marrow), technical innovations in the selection procedure and methotrexate (also using bone marrow). The main objective of and the use of total body irradiation (TBI), and anti-thymocyte this study is chronic GvHD relapse-free survival, a composite end- globulin (ATG) in the conditioning, significantly decreased this risk point that includes survival and, although indirectly, quality of life [7,16–18]. Also, more immunosuppressive drugs such as fludara- [31]. The accrual into this study finished in 2018 and results are bine and thiotepa have been recently incorporated into the condi- expected shortly. tioning chemotherapy, allowing to perform alloSCT with CD34+ selection without the use of ATG or TBI, and achieving similar rates of engraftment failure to those of unmodified transplants [19–21]. 3.3. Immune Reconstitution and Infection Immune reconstitution after transplantation depends on mul- 3.2. Graft-Versus-Host Disease tiple factors, including the conditioning regimen, type of graft and thymic activity of the recipient [17,32]. Patients undergoing The main goal of carrying out CD34+ cell selection is to decrease the alloSCT with CD34+ selection have delayed recovery of CD4+ T- risk of GvHD and, thus, the mortality and morbidity associated with cells (absolute and naïve), longer time for the CD4+/CD8+ ratio this frequent complication. Numerous studies have shown the ben- inversion, as well as delayed mitogenic T-cell response. In addition, efit of TCD transplants in terms of GvHD reduction. At the begin- these patients have less functionality of the T-cell receptor (TCR) ning of this decade, a multicenter phase II study conducted by the (thymic function marker) than those receiving unmodified grafts, Blood and Marrow Transplant Clinical Trials Network (BMT CTN although these differences disappear after 6–9 months of alloSCT 0303, NCT01119066) [5] including 44 patients with acute myeloid [33,34]. Similarly, a slower recovery of the TCRs has been observed leukemia (AML) in first or second complete remission and receiv- within the first year after alloSCT compared with unmodified grafts ing a CD34+ selected alloSCT showed an incidence of grade II– [35], whereas early recovery of T lymphocyte functionality has been IV acute GvHD and chronic GvHD at 2 years of 22.7% and 6.8%, associated with better survival in CD34+ selection alloSCT [36]. respectively. These incidences are significantly lower than those reported by using unmodified grafts for alloSCT in similar patient To overcome the caveat of delayed immune reconstitution, sev- populations. Subsequent retrospective studies including patients eral approaches have been proposed. Among them, a phase 1 study with AML [19,22–24], acute lymphoblastic leukemia (ALL) [25,26], (CYT107) carried out in patients with CD34+ selection alloSCT and myelodysplastic syndrome (MDS) [22,27] also demonstrated explored the role of interleukin-7 (IL-7) in the reconstitution and a lower incidence of acute and chronic GvHD compared to non- survival of T cells. The use of human recombinant IL-7 showed to manipulated transplants, in the context of myeloablative condition- be safe and, apparently effective in improving immune reconstitu- ing. In the reduced-intensity conditioning setting, a retrospective tion after transplant, by increasing the number and functionality study compared the use of CD34+ cell selection alloSCT with a non- of CD8+ and CD4+ T cells, without increasing the risk of GvHD manipulated reduced-intensity platform in patients with AML and [37]. Another proposed strategy to enhance immune reconstitu- MDS older than 50 years has been recently published. This report tion is the use of hormonal ablation with Gonadotropin-releasing also observed a lower incidence of grade 2–4 acute GvHD (18% hormone (GnRH) agonists to favor thymopoiesis (NCT01746849) vs 46%) and chronic GvHD (6% vs 55%) in the TCD arm [28]. [38,39]. Recently, a study of more than 500 patients with acute leukemia The aforementioned delay in the immune reconstitution is asso- comparing the ATG-based GvHD prophylaxis with CD34+ selected ciated with an increased risk of opportunistic infections within alloSCT showed lower incidence of acute and chronic GvHD in the the first 12 months after the procedure [40], especially viral latter group [29]. infections, including cytomegalovirus (CMV) [41,42], Epstein– Studies focused on GvHD in the context of CD34+ cell selected Barr virus (EBV), adenovirus (ADV), or Herpes virus 6 (HHV-6) transplants have not only confirmed these low incidences, but also Pdf_Folio:155 [43–45]. In a study of 156 patients who received alloSCT with 156 E. Roldan et al. / Clinical Hematology International 1(3) 154–160 CD34+ selection in one center, 85% developed at least one viremia immunosuppressive drugs, especially in patients over 55 years old in the first 100 days posttransplant [43]. receiving chemotherapy-based conditioning regimens [52]. CMV is the most frequent viral infection reported after CD34+ As for late complications, a recent landmark analysis on 276 patients selected alloSCT, and has an early presentation. In a study including who were alive and in complete remission after one year of CD34+ more than 200 patients [41], cumulative incidences of 85% and 62% alloSCT disclosed that ferritin levels >1,000 ng/mL, a lymphocyte were reported in CMV seropositive patients with seropositive or count <0.5 × 109 /L, and an albumin level of less than 4.0 g/dL seronegative donors, respectively. Additionally, 5% of the patients were associated with an increased risk of toxicity after one year. developed organ CMV disease. In the risk factor analysis, the risk of The overall survival of patients after one year post-SCT was 77% at CMV disease was associated with persistent positive viremia (more 4 years [53]. than 28 days). It is important to highlight that in this transplant plat- The most common GvHD prophylactic regimens include cal- form, seronegative patients receiving a transplant from seropositive cineurin inhibitors, methotrexate, or sirolimus, which contribute donors have a risk of transmission of CMV infection close to 0%, substantially to SCT toxicity. Methotrexate can be hepatotoxic, similarly to patients with a negative donor and recipient serology nephrotoxic, and, not uncommonly, causes mucositis and related [41]. To prevent CMV disease and infection, prophylactic or antic- complications. Calcineurin inhibitors pose serious risk of renal tox- ipated antiviral treatments with drugs such as letermovir [46] or icity after SCT and can cause hypertension, electrolyte disturbances, brincidofovir [47,48] have been studied in this platform. dyslipidemia, glucose intolerance, tremor, posterior reversible Regarding EBV, the reported incidences of infection and EBV- leukoencephalopathy syndrome, and thrombotic microangiopathy related posttransplant lymphoproliferative disorder (PTLD) are (TMA). Sirolimus has been associated with a higher risk of Hep- 15% and 5%, respectively, with a median time of presentation at atic veno-occlusive disease (VOD), Thrombotic microangiopathy week 14 after transplant [43]. A study with 405 patients comparing (TMA), and other endotelial-related complications [54,55]. ex-vivo TCD with T-cell repleted alloSCT showed a higher risk of The use of CD34+ selected HCT precludes the need for posttrans- PTLD in the TCD group (5% vs 1% [p = 0.018], respectively) [30]. plant GVHD prophylaxis, reducing transplant-related toxicity. It For ADV, the risk of infection in CD34+ cell selection alloSCT is also has the potential to open myeloablative SCT to elderly or also higher than with the use of unmodified grafts [44]. In a study comorbid patients who would otherwise have been excluded from with 215 patients undergoing a CD34+ selection SCT conducted SCT or offered a RIC approach. Hence, two recent studies have in a single center, 18 patients (8%) presented ADV viremia with shown a similar overall survival between patients older and younger a median appearance at 57 days [45]. One-third of these patients than 55–60 years old [56,57]. In another recent study in patients developed ADV organ disease. older than 50 years, the CD34+ cell selection platform was not asso- ciated with an increased risk of TRM compared with an unmod- Similarly, the risk of human HHV-6 infection is also higher than in ified reduced intensity conditioning (RIC) approach [28]. Also, it alloSCT with unmodified grafts, reaching an incidence up to 17%, has been confirmed that the HCT-CI [58] is useful to predict TRM although only 10% of patients require targeted treatment [43]. in patients receiving CD34+ selected grafts, and can be helpful Given the high incidence of these infections, alloSCT with TCD when deciding on the transplant indication for elderly or comorbid could be an ideal platform in which to expand the use of adaptive patients [59]. immunotherapy with specific T lymphocytes against viral infec- Finally, it has been demonstrated that the good performance status tions. Both nonspecific (directed to common viral pathogens) and of patients after CD34+ selected alloSCT and the low incidence of specific lymphocytes have been investigated in these patients with GvHD facilitate the administration and tolerability of antineoplas- promising results [49,50]. tic drugs after transplant, both prophylactically or as a treatment for disease relapse [60]. 3.4. Organ Toxicity TRM is the most limiting factor for a successful alloSCT, and may 3.5. Relapse prevent elderly or unfit patients to receive a potential curative ther- The main objective of alloSCT in malignant diseases is to decrease apy. TRM is mostly driven by GvHD and infections, as previously the risk of relapse through the graft-versus-leukemia (GvL) effect. discussed. In addition to them, direct organ toxicities can also ham- Since the latter is mostly mediated by T-cells, some concerns have per the success of the transplant procedure. been raised on the ability of CD34+ selected alloSCT to control dis- Recently, the toxic effects of the CD34+ cell selection alloSCT plat- ease relapse. The earlier reports using CD34+ selected grafts dis- form were analyzed in a cohort of 200 patients within the first year closed an increased risk of relapse in these patients [61]. However, after transplantation [51]. The most relevant toxicities in this period those studies used old CD34+ cell selection methods, and post- were infectious, metabolic, hematological, gastrointestinal, cardiac, transplant immunosuppression was routinely administered. Also, and pulmonary complications. Noteworthy, renal complications the main transplant indication in those studies was chronic myeloid were minimal and a low incidence of hepatic veno-occlusive disease leukemia (CML), which is a highly sensitive disease to the GvL was reported. Higher targeted busulfan levels, CMV seropositivity effect. A retrospective analysis compared the results of two groups of the recipient, and a high comorbidity index (HCT-CI ≥ 3) were of patients with CML in chronic phase receiving CD34+ selection associated with an increased risk of death from any cause. Another alloSCT (n = 46) and unmodified alloSCT (n = 40). The 3-year study showed that fluid overload continues to be a cause of mor- relapse incidence in the TCD group was 2.5 times higher than in bidity in CD34+ selection transplantation, despite the absence of Pdf_Folio:156 the group without depletion. However, most of these patients were E. Roldan et al. / Clinical Hematology International 1(3) 154–160 157 rescued with donor lymphocytes infusions (DLI). Due to the high and MDS [27] patients transplanted at MSKCC and MDACC with risk of relapse in this indication, the use of TCD alloSCT in CML is the same strategies also found a similar risk of relapse between currently not recommended [61]. the two groups. Finally, a recent study in patients older than 50 years with AML and MDS found a lower risk of relapse in those In contrast, several more contemporary studies have shown a receiving CD34+ selected grafts compared with RIC-alloSCT with similar risk of relapse in patients receiving CD34+ selected com- unmodified grafts [28]. This was probably because a higher inten- pared with unmodified grafts in several hematological malignan- sity conditioning regimen could be administered in the CD34+ cies, including AML [19,24], ALL [25,26], MDS [27], and in some selected cohort, since these patients do not have the additional tox- subtypes of non-Hodgkin’s lymphoma [62]. One of these reports icity from posttransplant immunosuppression. focused on patients with AML in first complete remission evaluat- ing the clinical outcome of 115 patients receiving CD34+ selected Donor lymphocyte infusions (DLI) have been used in this plat- alloSCT at Memorial Sloan Kettering Cancer Center (MSKCC) and form to stimulate the GvL effect, both as preemptive and as a 181 patients treated with unmodified alloSCT at M.D. Anderson therapeutic strategy. Bryant et al. [63] retrospectively reviewed Cancer Center (MDACC) [19]. This study observed a similar risk a cohort of 58 CD34+ selected patients who received DLI to of relapse at 1 year (17% vs 21%, p = 0.4) and at 3 years (18% vs treat overt relapse (n = 20), minimal residual disease [MRD] 25%, p = 0.9) between the two groups. Other analyses in ALL [25] (n = 11), or mixed chimerism (n = 27). Seventy-three percent of Table 2 Comparative studies of CD34+ selection alloSCT versus unmodified alloSCT. Cohort Donor Disease aGvHD Grade II-IV cGvHD (TCD vs UMT) DFS and OS (TCD vs UMT) (TCD vs UMT) AlloTCD 2 years DFS BMTCTN 54% vs 55% 0303 Pasquini n = 44 Identical 23% vs 39% 19% vs 50% AML et al. [64] sibling P = 0.07 p < 0.001 UM+IS BMT CTN 2 years OS 0101 65% vs 59% n = 84 AlloTCD Identical 3 years DFS MSKCC sibling 58% vs 60% n = 115 HLA 10/10 5% vs 18% 13% vs 53% Bayraktar URD AML p = 0.005 p < 0.001 et al. [19] UM+IS HLA 9/10 RD MDACC HLA 9/10 URD 3 years OS n = 181 57% vs 66% AlloTCD Identical 3 years DFS MSKCC sibling 43% vs 36% n = 52 HLA 10/10 17% vs 43% 14% vs 33% Hobbs and URD AAL p = 0.001 p = 0.006 Perales [26] UM+IS HLA 9/10 RD MDACC HLA 9/10 URD 3 years OS n = 115 43% vs 43% AlloTCD Identical Low risk Low risk 3 years DFS MSKCC sibling 13% vs 41% 5% vs 48% Low risk n = 60 HLA 10/10 p < 0.001 60% vs 53% Tamari URD MSD p = 0.015 High risk et al. [27] UM+IS HLA 9/10 RD 32% vs 11% n = 121 HLA 9/10 URD (MDACC) High risk High risk 3 years OS 16% vs 22% 0% vs 24% Low risk P = 0.75 p = 0.013 59% vs 54% High risk 36% vs 15% AlloTCD Identical 3 years DFS MSKCC sibling 55% vs 50% n = 204 HLA 10/10 AML 18% vs 46% 6% vs 55% Barba URD MSD p < 0.001 p < 0.001 et al. [28] UM+IS RIC. GETH 3 years OS N = 152 58% vs 56% Abbreviations: AlloTCD: AlloSCT with T cell depletion; UM: Unmodified; IS: Inmunosuppression; BMT CTN: Blood and Marrow Transplant Clinical Trials Network; MDACC: MD Ander- son Cancer Center; MSKCC: Memorial Sloan Kettering Cancer Center; MAC: myeloablative conditioning; aGvHD: acute Graft versus Host Disease; cGvHD: chronic graft-versus-host disease; AML: acute myeloid leukemia; MDS: myelodisplastic syndrome; ALL: acute lymphoblastic leukemia; RD: related donor; URD: Unrelated donor; EFS: event free survival; OS: overall survival; RIC: reduced intensity conditioning; GETH, Grupo Español de Trasplante Hematopoyético. Pdf_Folio:157 158 E. Roldan et al. / Clinical Hematology International 1(3) 154–160 patients with MRD achieved remission, versus 15% in those with AUTHORS’ CONTRIBUTIONS overt relapse. DLI was associated with low rates of acute (3%) and chronic (7%) GvHD indicating that it could be an effective strategy MAP and PB conceived the manuscript. All authors wrote and to manage relapse, especially in patients with MRD+ disease. reviewed the manuscript. 3.6. Survival FUNDING STATEMENT Most of the comparative studies have shown a similar overall sur- PB received funding from the Carlos III FIS16/01433 Health vival between CD34+ cell selection SCT and unmodified trans- Institute and a PERIS 2018–2020 grant from the Generalitat plants in different diseases and conditioning intensities (Table 2). de Catalunya (BDNS357800). MAP received funding from the Again, the results of the prospective BMT CTN (NCT02345850) National Institutes of Health (Grant P01 CA23766 and NIH/NCI clinical trial are awaited and will help to clarify the role of cancer Center Support Grant P30 CA008748). 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