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Expert Opinion on Biological Therapy Mar 2010Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many hematological malignancies and genetic disorders. The majority of patients do not have... (Review)
Review
IMPORTANCE OF THE FIELD
Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many hematological malignancies and genetic disorders. The majority of patients do not have a human leukocyte antigen (HLA) identical sibling donor, and alternative stem cell sources include HLA-matched or mismatched unrelated donors and haploidentical related donors. However, alternative donor HSCT are associated with three major complications i) graft rejection; ii) graft-versus-host disease (GvHD); and iii) delayed immune reconstitution leading to viral infections and relapse.
AREAS COVERED IN THIS REVIEW
Graft rejection and the risk of GvHD can be significantly reduced by using intensive conditioning regimens, including in vivo T cell depletion as well as ex vivo T cell depletion of the graft. However, the benefits of removing alloreactive T cells from the graft are offset by the concomitant removal of T cells with anti-viral or anti-tumor activity as well as the profound delay in endogenous T cell recovery post-transplant. Thus, opportunistic infections, many of which are not amenable to conventional small-molecule therapeutics, are frequent in these patients and are associated with significant morbidity and high mortality rates. This review discusses current cell therapies to prevent or treat viral infections/reactivations post-transplant.
WHAT THE READER WILL GAIN
The reader will gain an understanding of the current state of cell therapy to prevent and treat viral infections post-HSCT, and will be introduced to preclinical studies designed to develop and validate new manufacturing procedures intended to improve therapeutic efficacy and reduce associated toxicities.
TAKE HOME MESSAGE
Reconstitution of HSCT recipients with antigen-specific T cells, produced either by allodepletion or in vitro reactivation, can offer an effective strategy to provide both immediate and long-term protection without harmful alloreactivity.
Topics: Adoptive Transfer; Blood Donors; Hematopoietic Stem Cell Transplantation; Humans; Lymphocyte Depletion; T-Lymphocytes, Cytotoxic; Virus Diseases
PubMed: 20132056
DOI: 10.1517/14712590903456003 -
Transplantation and Cellular Therapy Dec 2021Allogeneic hematopoietic stem cell transplantation (SCT) is the sole established curative treatment option for patients with sickle cell disease (SCD). However, a lack... (Meta-Analysis)
Meta-Analysis Review
Allogeneic hematopoietic stem cell transplantation (SCT) is the sole established curative treatment option for patients with sickle cell disease (SCD). However, a lack of HLA-identical sibling donors is a limiting factor. Haploidentical related donors are a promising donor pool, potentially extending SCT as a curative treatment option to a larger group of patients with no other meaningful treatment options for their severe SCD. In the present study, we aimed to systematically review the results of haploidentical SCT in patients with SCD. A comprehensive search was performed in MEDLINE/PubMed and Embase up to May 2021. Data were extracted by 2 reviewers independently, and the Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the studies. Fourteen studies met our inclusion criteria. To provide an overview of the results of haploidentical SCT, we grouped the studies into myeloablative conditioning versus nonmyeloablative conditioning as well as into in vitro versus in vivo (ie, with post-transplantation cyclophosphamide) T cell depletion with a subgroup meta-analysis of proportions. All the included studies were observational cohort studies. Only 3 of these studies reported data for both matched sibling donor (MSD) SCT and haploidentical SCT. Based on a comparative meta-analysis of the 3 studies that included both haploidentical and MSD transplantation, graft failure was significantly higher in the haploidentical group than in the MSD group (odds ratio, 5.3; 95% confidence interval [CI], 1.0 to 27.6). Overall survival was not significantly different between the groups. A subgroup meta-analysis of the results of haploidentical SCT showed relatively low overall pooled proportions of graft failure (7%; 95% CI, 2% to 20%), acute graft-versus-host disease (GVHD) (4%; 95% CI, 2% to 12%), and chronic GVHD (11%; 95% CI, 7% to 16%). Overall survival (OS) was high in all the included studies (91%; 95% CI, 85% to 94%). Adjustments to the conditioning regimens, robust pretransplantation and post-transplantation T cell depletion, and improved supportive care have resulted in reduced graft failure and improved OS following haploidentical SCT in patients with SCD. We conclude that the safety of haploidentical SCT in SCD patients has improved significantly, and that this should be considered as a curative option in patients with severe SCD.
Topics: Anemia, Sickle Cell; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Transplantation Conditioning
PubMed: 34537420
DOI: 10.1016/j.jtct.2021.09.009 -
Transplantation and Cellular Therapy Apr 2022Haploidentical (haplo) donor grafts are a well-established alternative donor source for allogeneic hematopoietic cell transplantation (HCT); however, data comparing...
Haploidentical (haplo) donor grafts are a well-established alternative donor source for allogeneic hematopoietic cell transplantation (HCT); however, data comparing health-realted quality of life (HRQOL) measures between haplo-HCT and HCT using other donor sources are lacking. We hypothesized that post-transplantation HRQOL might not differ between haplo-HCT and HCT with other graft sources. We conducted a single-institution retrospective analysis comparing HRQOL of haplo-HCT with matched-related donor (MRD) HCT and matched unrelated donor (MUD) HCT for hematologic diseases. We included 90 haplo, 102 MRD, and 229 MUD adult first allogeneic HCTs performed between May 2014 and December 2019. HRQOL for haplo-HCT, MRD-HCT, and MUD-HCT were compared separately for myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC). HRQOL was assessed using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale pretransplantation and at days +100 and +180 post-transplantation. MAC haplo-HCT showed no difference in all domains of HRQOL and other transplantation outcomes, including overall survival, compared with MAC MRD/MUD-HCT, except for a higher incidence of non-cytomegalovirus infections (P = .003). RIC haplo-HCT was associated with significantly better emotional well-being (P = .008) and functional well-being (P = .011) compared with MUD-HCT. RIC haplo-HCT was associated with higher rates of non-cytomegalovirus infections (P < .001) and relapse mortality (P = .044) but a lower rate of nonrelapse mortality (P = .008) compared with RIC MUD-HCT. Haplo-HCT had comparable total HRQOL scores and overall survival to MRD/MUD-HCT in both the MAC and RIC cohorts. Interrogation of HRQOL among disease-specific groups may further elucidate the existence of any additional benefits with these different transplantation modalities.
Topics: Adult; Hematopoietic Stem Cell Transplantation; Humans; Quality of Life; Retrospective Studies; Transplantation Conditioning; Unrelated Donors
PubMed: 35074556
DOI: 10.1016/j.jtct.2022.01.012 -
Frontiers in Immunology 2022Haploidentical donor stem cell transplantation (HID-SCT) based on antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis had achieved a similar...
Haploidentical donor stem cell transplantation had a lower incidence of bronchiolitis obliterans syndrome compared with HLA-matched sibling donor transplantation in patients with hematologic malignancies: Benefit from ATG?
BACKGROUND
Haploidentical donor stem cell transplantation (HID-SCT) based on antithymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis had achieved a similar incidence of chronic graft-versus-host disease (cGVHD) with human leukocyte antigen (HLA)-matched sibling donor stem cell transplantation (MSD-SCT). However, bronchiolitis obliterans syndrome (BOS), which serves as pulmonary cGVHD, was rarely compared between HID and MSD transplantation.
METHODS
One thousand four hundred five patients with hematologic malignancies who underwent allogeneic SCT were enrolled in this retrospective study. Based on donor type, we divided the patients into three groups: HID, MSD, and match unrelated donor (MUD) groups. The cumulative incidences and risk factors of BOS were analyzed.
RESULTS
The 5-year cumulative incidence of BOS was 7.2% in the whole population. HID transplantation had a lower 5-year cumulative incidence of BOS than MSD transplantation (4.1% vs. 10.0%, p < 0.001) and a similar incidence with MUD transplantation (4.1% vs. 6.2%, p = 0.224). The 5-year cumulative incidence of BOS was lower in the ATG group than that in the non-ATG group in both the whole and MSD populations (4.6% vs. 11.2%, p < 0.001, and 4.1% vs. 11.2%, p = 0.042, respectively). The 5-year incidence of BOS in mixed grafts [peripheral blood stem cell (PBSC) plus bone marrow] group was also lower than that in the PBSC group (4.2% vs. 9.1, p = 0.001). Multivariate analysis showed that HID, ATG, and mixed grafts were protective factors for BOS [odds ratio (OR) 0.3, 95% CI 0.2-0.6, p < 0.001; OR 0.3, 95% CI 0.2-0.7, p = 0.001; OR 0.3, 95% CI 0.1-0.8, p = 0.013], and acute graft-versus-host disease (aGVHD) and cGVHD were independent risk factors for BOS (OR 2.1, 95% 1.1-4.3, p = 0.035; OR 10.1, 95% CI 4.0-25.0, p < 0.001).
CONCLUSIONS
HID transplantation had a lower incidence of BOS than MSD transplantation, which might be associated with ATG and mixed grafts.
Topics: Humans; Antilymphocyte Serum; Graft vs Host Disease; Incidence; Siblings; Transplantation Conditioning; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Hematologic Neoplasms; HLA Antigens; Bronchiolitis Obliterans; Unrelated Donors; Histocompatibility Antigens Class II
PubMed: 36389692
DOI: 10.3389/fimmu.2022.1036403 -
Transplantation and Cellular Therapy Mar 2023When using post-transplantation cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis for lymphoma patients, it is currently unknown whether a matched...
When using post-transplantation cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis for lymphoma patients, it is currently unknown whether a matched unrelated donor (MUD) or a haploidentical related donor is preferable if both are available. In this study we wanted to test whether using a haploidentical donor has the same results of a MUD. A total of 2140 adults (34% Center for International Blood and Marrow Transplant Research, 66% European Society for Blood and Marrow Transplantation registry) aged ≥18 years who received their first haploidentical hematopoietic cell transplantation (haplo-HCT) or MUD-HCT (8/8 match at HLA-loci A, B, C, and DRB1) for lymphoma using PTCy-based GVHD prophylaxis from 2010 to 2019 were retrospectively analyzed. The majority of both MUD and haploidentical HCTs received reduced intensity/nonmyeloablative conditioning (74% and 77%, respectively) and used a peripheral blood stem cell graft (91% and 60%, respectively) and a 3-drug GVHD prophylaxis (PTCy + calcineurin inhibitor + MMF in 54% and 90%, respectively). Haploidentical HCT has less favorable results versus MUD cohort in terms of overall mortality (hazard ratio [HR= = 1.69; 95% confidence interval [CI], 1.30-2.27; P < .001), progression-free survival (HR=1.39; 95% CI, 1.10-1.79; P = .008), nonrelapse mortality (HR = 1.93; 95% CI, 1.21-3.07; P = .006), platelet engraftment (HR = 0.69; 95% CI, 0.59-0.80; P < .001), acute grade 2-4 GVHD incidence (HR = 1.65; 95% CI, 1.28-2.14; P < .001), and chronic GVHD (HR = 1.79; 95% CI, 1.30-2.48, P < .001). No significant differences were observed in terms of relapse and neutrophil engraftment. Adjusting for propensity score yielded similar results. Whenever MUD is available in a timely manner, it should be preferred over a haploidentical donor when using PTCy-based GVHD prophylaxis for patients with lymphoma.
Topics: Adult; Humans; Adolescent; Unrelated Donors; Retrospective Studies; Neoplasm Recurrence, Local; Cyclophosphamide; Lymphoma; Graft vs Host Disease
PubMed: 36577482
DOI: 10.1016/j.jtct.2022.11.028 -
Hematology/oncology and Stem Cell... Dec 2020Allogeneic hematopoietic stem cell transplantation (HSCT) is, to date, the only curative treatment for sickle cell disease (SCD). Because an human leukocyte antigen... (Review)
Review
Allogeneic hematopoietic stem cell transplantation (HSCT) is, to date, the only curative treatment for sickle cell disease (SCD). Because an human leukocyte antigen (HLA)-matched sibling donor is not always available, alternative stem cell sources such as unrelated or haploidentical related donors have been explored. To date, few series of SCD patients transplanted with an unrelated donor, cord blood, and haploidentical related donor have been reported, but the high rates of rejection and chronic graft versus host disease have limited their widespread application. We describe the outcomes of a retrospective, registry-based, survey on 144 alternative donor HSCT performed for SCD in 30 European Society for Blood and Marrow Transplantation centers between 1999 and 2017. Data on 70 unrelated adult donors (49%), six cord blood (4%), and 68 haploidentical donors (47%; including post-HSCT Cy, ex vivo T-cell depleted, and other haplo-HSCTs) were reported and missing information was updated by the centers. Overall, 16% patients experienced graft failure, Grade II-IV acute GVHD at 100 days was 24%, whereas Grade III-IV was 10%. Chronic GVHD was observed in 24% (limited for 13 patients and extensive for 18 patients). Overall, the 3-year overall survival (OS) was 86% ± 3% and 3-year event-free survival (EFS; considering death and graft failure as events) was 72% ± 4%. We therefore conclude that alternative donor HSCT for SCD can be feasible but efforts in decreasing relapse and GVHD should be promoted to increase its safe and successful utilization. Moreover, a better knowledge of HLA matching and the tailoring of conditioning could help improve EFS and OS.
Topics: Adolescent; Adult; Aged; Anemia, Sickle Cell; Child; Child, Preschool; Disease-Free Survival; Europe; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphocyte Depletion; Male; Middle Aged; Survival Rate; Transplantation Conditioning; Unrelated Donors
PubMed: 32201153
DOI: 10.1016/j.hemonc.2019.12.011 -
Frontiers in Immunology 2023Donor-specific antibodies (DSAs) are IgG allo-antibodies against mismatched donor HLA molecules and can cause graft failure (GF) in the setting of haploidentical...
BACKGROUND
Donor-specific antibodies (DSAs) are IgG allo-antibodies against mismatched donor HLA molecules and can cause graft failure (GF) in the setting of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Our aim was to report the experience of the Spanish Group of Hematopoietic Transplant (GETH-TC) in DSA-positive patients who had undergone haplo-HSCT.
METHODS
We conducted a survey of patients who underwent haplo-HSCT in GETH-TC centers between 2012 and 2021. Data were collected on the DSA assay used, monitoring strategy, complement fixation, criteria for desensitization, desensitization strategies and transplant outcomes.
RESULTS
Fifteen centers from the GETH-TC responded to the survey. During the study period, 1,454 patients underwent haplo-HSCT. Seventy of the transplants were performed in 69 DSA-positive patients, all of whom lacked a suitable alternative donor; 61 (88%) patients were female (90% with prior pregnancies). All patients received post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis. Regarding baseline DSA intensity, 46 (67%) patients presented mean fluorescence intensity (MFI) >5,000, including 21 (30%) with MFI >10,000 and three (4%) with MFI >20,000. Six patients did not receive desensitization treatment, four of them with MFI <5,000. Of 63 patients receiving desensitization treatment, 48 (76%) were tested after desensitization therapy, and a reduction in intensity was confirmed in 45 (71%). Three patients (5%) experienced an increase in MFI after desensitization, two of whom experienced primary GF. Cumulative incidence of neutrophil engraftment at day 28 was 74% in a median of 18 days (IQR, 15─20); six patients died before engraftment due to toxicity or infection and eight patients had primary GF despite desensitization in seven of them. After a median follow-up of 30 months, two-year overall and event-free survival were 46.5% and 39%, respectively. The two-year cumulative incidence of relapse was 16% and non-relapse mortality (NRM) was 43%. Infection was the most frequent cause of NRM, followed by endothelial toxicity. Multivariate analysis identified baseline MFI >20,000 as an independent risk factor for survival and an increase in titers after infusion as an independent risk factor for GF.
CONCLUSIONS
Haplo-HSCT is feasible in DSA-positive patients, with high rates of engraftment after desensitization guided by DSA intensity. Baseline MFI >20,000 and increased intensity after infusion are risk factors for survival and GF.
Topics: Pregnancy; Humans; Female; Male; Transplantation, Haploidentical; Tissue Donors; Hematopoietic Stem Cell Transplantation; Cell- and Tissue-Based Therapy; Immunoglobulin G
PubMed: 37304258
DOI: 10.3389/fimmu.2023.1165759 -
Cancer Medicine Sep 2020Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic option for patients with acute myeloid leukemia (AML) or...
Haploidentical related donor vs matched sibling donor allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome aged over 50 years: A single-center retrospective study.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic option for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Increasing data suggest that haploidentical donor (HID) transplantation achieve comparable outcomes with HLA-matched sibling donor (MSD) in adult AML/MDS. This retrospective study compared the outcomes of AML or MDS patients age ≥50 years underwent HID and MSD transplantation. One hundred and fifty-six patients were enrolled in this study, including 75 HID and 81 MSD transplantation. The 100-day cumulative incidence of II-IV° acute graft-versus-host disease (GVHD) was 33.3 ± 5.4% vs 22.2 ± 4.6%, respectively, in HID and MSD groups (P = .066), and III-IV° acute GVHD was not significantly different between two groups (5.3%±2.6% vs 6.2%±2.7%, respectively, P = .823). The 2-year cumulative incidence of limited and extensive chronic GVHD was not statistically different in HID and MSD groups (20.9 ± 5.5% vs 18.9 ± 4.8% and 13.0 ± 4.7% vs 19.7 ± 5.0%, P = .889 and P = .269, respectively). The 2-year cumulative incidences of relapse (27.0 ± 5.6% vs 22.7 ± 5.1%, P = .509), 2-year overall survival (63.0 ± 5.8% vs 66.7 ± 5.4%, P = .454), 2-year transplant-related mortality (17.2 ± 4.6% vs 17.4 ± 4.4%, P = .847), 2-year progression-free survival (59.3 ± 5.8% vs 64.5 ± 5.4%, P = .437), 2-year GVHD-free relapse-free survival (42.6 ± 5.9% vs 40.9 ± 5.6%, P = .964) were not significantly different in the two groups. The present data showed equivalent outcomes in AML or MDS patients age ≥50 years underwent HID and MSD transplantation.
Topics: Acute Disease; Age Factors; Aged; Cause of Death; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histocompatibility; Humans; Incidence; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Progression-Free Survival; Recurrence; Retrospective Studies; Siblings; Time Factors; Tissue Donors; Transplantation Conditioning
PubMed: 32686915
DOI: 10.1002/cam4.3290 -
Frontiers in Immunology 2020Following allogeneic blood and marrow transplantation (BMT), graft-versus-host disease (GvHD) continues to represent a significant cause of treatment failure, despite... (Review)
Review
Following allogeneic blood and marrow transplantation (BMT), graft-versus-host disease (GvHD) continues to represent a significant cause of treatment failure, despite the routine use of conventional, mainly calcineurin inhibitor-based prophylaxis. Recently, post-transplant cyclophosphamide (PTCy) has emerged as a safe and efficacious alternative. First, omitting the need for T-cell depletion in the setting of haploidentical transplantation, growing evidence supports PTCy role in GvHD prevention in matched-related and matched-unrelated transplants. Through improved understanding of GvHD pathophysiology and advancements in drug development, PTCy emerges as a unique opportunity to design calcineurin inhibitor-free strategies by integrating agents that target different stages of GvHD development.
Topics: Animals; Bone Marrow Transplantation; Cyclophosphamide; Graft vs Host Disease; HLA Antigens; Histocompatibility; Histocompatibility Testing; Humans; Immunosuppressive Agents; Postoperative Complications; Transplantation, Haploidentical; Unrelated Donors
PubMed: 32373119
DOI: 10.3389/fimmu.2020.00636 -
Biology of Blood and Marrow... Nov 2016More than 1% of the Japanese population has HLA-homozygous haplotypes. For patients with such haplotypes, HLA-haploidentical family members who have no HLA mismatch in...
More than 1% of the Japanese population has HLA-homozygous haplotypes. For patients with such haplotypes, HLA-haploidentical family members who have no HLA mismatch in the graft-versus-host direction are readily available donor candidates for hematopoietic cell transplantation (HCT). In this study, the outcomes of patients with homozygous HLA-A, -B, and -DRB1 antigens who received HCT without T cell depletion from a haploidentical related donor with mismatches in the host-versus-graft direction only (hetero-to-homo, n = 78) or from an HLA-matched sibling donor (MSD) (MSD-homo, n = 153) were compared with those in patients with heterozygous haplotypes who received HCT from an MSD (MSD-hetero, n = 7242). Transplant outcomes in the hetero-to-homo group were similar to those in the MSD-hetero group regarding neutrophil engraftment, grades III to IV acute graft-versus-host disease (aGVHD), nonrelapse mortality (NRM), relapse, and overall survival. On the other hand, the incidences of severe aGVHD and NRM in the MSD-homo group were significantly lower than those in the MSD-hetero group (grades III to IV aGVHD: aHR .50, P = .034; NRM: aHR .48, P = .004). In conclusion, patients with HLA-homozygous haplotypes achieved lower GVHD and NRM rates for MSD transplantation than those with HLA-heterozygous haplotypes. When an MSD or an appropriate alternative donor is not available for patients with HLA-homozygous haplotypes who need immediate transplantation, transplantation from a haploidentical donor without T cell depletion is a viable option, given the comparable transplant outcomes for hetero-to-homo HCT and MSD-hetero HCT.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Genotype; Graft Survival; Graft vs Host Disease; HLA Antigens; Haplotypes; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Male; Middle Aged; Recurrence; Siblings; Survival Analysis; Tissue Donors; Transplantation, Haploidentical; Treatment Outcome; Young Adult
PubMed: 27492794
DOI: 10.1016/j.bbmt.2016.07.020